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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Willing and able to give written informed consent for participation in the study
2. Age range 50-65 years
3. Menopausal status (defined by \>1 yr since last menstrual period or follicle stimulating hormone (FSH) level in the postmenopausal range)
4. Ambulatory
5. Body mass Index (BMI) must be ≥ 18 and ≤ 32 kg/m2 at screening
6. 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
7. Commitment not to use any products that may influence the study outcome
8. Ability to understand and comply with the requirements of the study

Exclusion Criteria:

1. Premenopausal status
2. History of \>1 previous atraumatic bone fractures after age 50
3. Presence of established osteoporosis (T-score ≤ - 2.5, in the lumbar spine, femoral neck or total hip as measured by screening DEXA)
4. 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
5. Uncontrolled type II diabetes mellitus (HgbA1c ≥ 7% within the last 12 months)
6. History of bariatric surgery or other forms of malabsorption (including documented celiac disease, or chronic diarrhea)
7. Alcohol abuse
8. 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)
9. Clinically significant cardiovascular disease (myocardial infarction, cerebral vascular accident or acute congestive heart failure within the previous 12 months
10. Any malignancies, other than localized skin squamous cell carcinoma, diagnosed within the previous 5 years, or any history of metastatic cancer
11. History of use of oral supplement products containing probiotic bacteria (more than once per week) within four weeks prior to baseline
12. 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
13. Use of oral or injectable bisphosphonates for more than 1 year within the last 5 years
14. 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
15. Use of antibiotics during the previous two months or frequent user of antibiotics (\>2 courses during the previous 12 months) for any cause
16. Smoking or use of nicotine-containing products during the last six months
17. Known hypersensitivity to any of the ingredients in the VSL#3 or the placebo study drug
18. serum or plasma 25-hydroxyvitamin D \[25(OH)D\] concentration \< 12 ng/mL
19. 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)