Effect of VSL#3 on Bone Mineral Density in Postmenopausal Women

Study Overview
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Brief Summary
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Osteoporosis has a devastating impact on quality of life of postmenopausal women, and is a significant cause of disability and morbidity. Many drugs are approved for the prevention and treatment of osteoporosis, but are associated with high costs and side effects. Some data from animal studies suggests that supplementation with probiotics can safely treat and prevent osteoporosis. The probiotic VSL#3 is commercially available, is safe for human consumption, and has been widely used in human clinical trials, and has known health-promoting effects in both children and adults. The double-blind, randomized, placebo-controlled trial of VSL#3 will be conducted for 12 months in 40 postmenopausal women to determine if VSL#3 improves bone mineral density and related bone markers. Study visits will include all or some of the following procedures: a medical exam, urine collection, height and weight measurement, a blood draw to assess bone biomarkers, a DEXA (dual energy X-ray absorptiometry) scan to measure bone density, and health questionnaires. This is one of the first clinical trials proposed to investigate the effects of probiotics in bone in humans. If successful, this proposal will provide the first evidence that nutritional supplementation with the probiotic VSL#3 is a safe and effective strategy for preventing postmenopausal bone loss.

Detailed Description
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Osteoporosis has a devastating impact on quality of life of postmenopausal women, and is a significant cause of disability and morbidity. Many drugs are approved for the prevention and treatment of osteoporosis, but are associated with high costs and side effects. Some data from animal studies suggests that supplementation with probiotics can safely treat and prevent osteoporosis. The probiotic VSL#3 is commercially available, is safe for human consumption, and has been widely used in human clinical trials, and has known health-promoting effects in both children and adults. The double-blind, randomized, placebo-controlled trial of VSL#3 will be conducted in a population of ambulatory, otherwise healthy, postmenopausal women for 12 months. Control and VSL#3-treated postmenopausal women will be matched by age (± 3 years). Study visits will include all or some of the following procedures: a medical exam, urine collection, height and weight measurement, a blood draw to assess bone biomarkers, a dual energy X-ray absorptiometry (DEXA) scan to measure bone density, and health questionnaires. The primary endpoint is the change in bone mineral density (BMD) at the L1-4 lumbar spine over one year of study. Changes in BMD at the femoral neck and total hip area will be secondary endpoints. All BMD data will also be used as a tool for future studies power calculation and design. Additional endpoints will include changes in bone turnover markers and inflammatory/osteoclastogenic cytokines. Measurements of indices of bone turnover and cytokine levels will provide much needed mechanistic information.The data will allow to establish whether VSL#3 prevents bone loss and/or increases bone mass by regulating bone resorption, formation, or both.

Official Title
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Effect of VSL#3 on Bone Mineral Density in Postmenopausal Women: a Pilot Randomized, Placebo-Controlled Trial

Conditions
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Menopausal Osteoporosis

Intervention / Treatment
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* Drug: VSL#3
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study Age range 50-65 years Menopausal status (defined by >1 yr since last menstrual period or follicle stimulating hormone (FSH) level in the postmenopausal range) Ambulatory Body mass Index (BMI) must be ≥ 18 and ≤ 32 kg/m2 at screening Bone mineral density (BMD), expressed as T-scores, must be > - 2.5 in the lumbar spine (L1-L4), the femoral neck, and the total hip, as measured by DEXA Commitment not to use any products that may influence the study outcome Ability to understand and comply with the requirements of the study Exclusion Criteria: Premenopausal status History of >1 previous atraumatic bone fractures after age 50 Presence of established osteoporosis (T-score ≤ - 2.5, in the lumbar spine, femoral neck or total hip as measured by screening DEXA) History of immunological or bone-related disorders including: HIV infection, Type I diabetes mellitus, bone marrow or organ transplantation; Inflammatory bowel disease (ulcerative colitis, Crohn's disease); multiple myeloma; osteomalacia; osteosarcoma; Paget's disease; rheumatoid arthritis; systemic lupus erythematous; parathyroid disorders Uncontrolled type II diabetes mellitus (HgbA1c ≥ 7% within the last 12 months) History of bariatric surgery or other forms of malabsorption (including documented celiac disease, or chronic diarrhea) Alcohol abuse Clinically significant chronic kidney disease (stage ≥ 2, with total serum creatinine level > 2.5 mg/dL and calculated glomerular filtration rate (GFR) < 60 mL/min by the Modification of Diet in Renal Disease (MDRD equation) Clinically significant cardiovascular disease (myocardial infarction, cerebral vascular accident or acute congestive heart failure within the previous 12 months Any malignancies, other than localized skin squamous cell carcinoma, diagnosed within the previous 5 years, or any history of metastatic cancer History of use of oral supplement products containing probiotic bacteria (more than once per week) within four weeks prior to baseline Current use (within the past 8 weeks) of any medication with known influences on the immune or skeletal system (e.g. immune modulation therapy, systemic glucocorticoids, systemic steroid hormones Use of oral or injectable bisphosphonates for more than 1 year within the last 5 years Current or past use (within 1 year) of Denosumab, Teriparatide, Raloxifene, hormone replacement therapy (HRT), calcitonin, or any other anti-resorptive agent other than bisphosphonates used for the prevention and treatment of osteoporosis Use of antibiotics during the previous two months or frequent user of antibiotics (>2 courses during the previous 12 months) for any cause Smoking or use of nicotine-containing products during the last six months Known hypersensitivity to any of the ingredients in the VSL#3 or the placebo study drug serum or plasma 25-hydroxyvitamin D [25(OH)D] concentration < 12 ng/mL uncontrolled thyroid disease (abnormal blood thyroid stimulating hormone (TSH) level within the last 12 months and/or changing dose of thyroid replacement therapy within the last 12 months)

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VSL#3<br>VSL#3 two active sachets [containing 450x109 colony-forming units (CFU)/sachet], taken daily in a single administration. | Drug: VSL#3<br>* 8 strains of live bacteria: Bifidobacterium breve, B. longum, B. infantis, L. acidophilus, L. plantarum, L. paracasei, L. bulgaricus and Streptococcus thermophilus. 900 billion CFU taken orally daily in a single administration.<br>|
| Placebo Comparator: Control<br>Placebo, no supplemental probiotics. | Other: Placebo<br>* Two placebo sachets taken orally daily in a single administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bone Mineral Density (BMD) of the Lumbar Spine (L1-L4 Segment) as Measured by Dual Energy X-ray Absorptiometry (DEXA) | All DEXA scans will be performed on the same device using a GE Lunar iDEXA machine. Participants will be asked to lie still on a scanning table with their arms at their sides for approximately 10 minutes. | Baseline and 12-month visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bone Density of the Non-dominant Hip (Femoral Neck and Total Hip Area) as Measured by DEXA (Dual Energy X-ray Absorptiometry). | All DEXA scans will be performed on the same device using a GE Lunar iDEXA machine. Participants will be asked to lie still on a scanning table with their arms at their sides for approximately 10 minutes. | Baseline and 12-month visit. | 
| Change in Serum Collagen Type 1 Cross-linked C-telopeptide (CTX) Concentrations (a Marker of Bone Resorption). | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Change in Serum Procollagen Type I N Propeptide (PINP) - a Marker of Bone Formation - Concentrations. | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Change in Serum Free Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) Concentrations. | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Change in Serum Osteoprotegrin (OPG) Concentrations. | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Change in Serum Tumor Necrosis Factor (TNF) | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Change in Serum Interleukin-17 (IL-17) Concentrations. | Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein. | Baseline, 6-month, 12-month visits | 
| Number of Unused Study Drug Sachets. | This will be determined by contacts (twice monthly telephone or at research center visits) of the study coordinator with each subject and responses to three standardized question areas: 1) Are you having any difficulty, problems or new symptoms with the study medication? 2) If yes, What has the problem been? and 3) Have you missed any of your study drug doses, and if so how many in the previous 2 week period? Appropriate notations based on subject responses will be documented in the case report form (CRF). Subjects will be instructed at study entry and reminded via serial contacts to return all of their used and unused drug sachets at each research center visit. Unused and used study drug sachets will be tallied and recorded in the CRF by the study coordinator serially for the entire study. | Every two weeks during the study 12-months | 
| Gastrointestinal Symptom Rating | Study drug tolerance will be assessed by obtaining serial measures of the Gastrointestinal Symptom Rating Scale (GSRS). These will be obtained with in-person interviews at the baseline and month 6 and 12 visits and by telephone contact with all subjects by the study coordinator every 2 weeks. Data will be analyzed within the 5 symptom domains depicting symptoms related to gastric reflux, abdominal pain, indigestion, diarrhea, and constipation.The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. A GSRS total score, the sum of all 5 domains, will also be assessed. | Every two weeks during the study 12-months | 
| Study Retention Rate. | The number of participants who complete all study visits, phone calls, and maintain drug compliance. Retention will be documented via conventional Consolidated Standards of Reporting Trials (CONSORT) criteria and documentation of missed study visits, missed telephone communications and compliance with study drug administration. All data will be maintained in the CRFs. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotics, Menopausal Osteoporosis