OsteoPreP: Food Supplements for Postmenopausal Bone Health

Australian Catholic University160 enrolled

Overview

To evaluate the effect of 12 months of supplementation with a probiotic (probiotic plus prebiotic; 2 capsules per day) on relative change (%) in total volumetric bone density (measured using high resolution peripheral quantitative computed tomography \[HR-pQCT\]) of the distal tibia.

It is well established that bone loss occurs throughout life after the attainment of peak bone mass which is usually reached by the end of the second decade of life. During the first 5-8 years following menopause, women experience an accelerated bone loss, which is then followed by a slower phase of decline in bone mineral density (BMD). As over 40% of all women in Australia will suffer an osteoporotic (fragility) fracture in their lifetime, investigating interventions that can prevent bone loss in postmenopausal women is a critical focus. The menopausal transition is also associated with an increased risk of cardiovascular disease, diabetes, and cognitive decline. These conditions and their treatments can also affect bone health. Previous research has indicated a potential link between the gut microbiome and bone health. Animal studies indicate that interventions affecting the gut microbiome may be successful in reducing bone loss, but human data is limited. Moreover, there is an emerging body of evidence linking the gut microbiome to cognitive, muscle and cardiometabolic function. Such studies indicate that probiotics (healthy gut bacteria) or prebiotics (food for healthy bacteria, e.g. fibre) can increase the amount of short chain fatty acids - such as butyrate -produced by the bacteria in the gut which may mediate the beneficial effects of improving gut health. The proposed study is a double-blind, placebo-controlled randomised trial, which will investigate whether consuming a probiotic supplement containing inulin (a prebiotic soluble fibre) twice daily for 12 months will improve bone health in postmenopausal women. In addition, secondary outcomes will measure the effect of the intervention on immune system modulation and cognition as well as musculoskeletal and metabolic function as potential mediators. One hundred and sixty postmenopausal women residing in Melbourne (Victoria, Australia) who are at least one year from their final menses will be recruited from the community via a mail out, advertisements in newspapers, social media, flyers as well as a landing page on an ACU managed website. The investigators have also applied for assisted mail outs through Services Australia for recruitment purposes. Services Australia is able to extract names and addresses of some target study demographics (females living in Melbourne aged between 40 and 65) from the Medicare database and mail them the study details on our behalf. Those wishing to participate will undergo a series of baseline assessments inclusive of bone mineral density scans, blood and stool sampling and physical activity and lifestyle questionnaires. They will then be randomised, in a blinded fashion, to consume one of the following two supplements: * Placebo control group (n = 80): Placebo capsule - 2 capsules per day * Probiotics group (n=80): Probiotic capsule - 2 capsules per day Study outcomes will be measured at baseline, 6 months, and 12 months. In addition, participants will be contacted via the telephone and email at three-month and nine-month timepoints to report any adverse responses to the supplementation. At the 12-month time point, participants will cease supplementation and immediately (within 24 hours) attend a post intervention assessment and will complete identical assessment measures to those they did at baseline. Finally, at 2 weeks post supplementation cessation participants will be asked to attend an appointment to provide a final stool sample. If it can be confirmed that long term consumption of a probiotic supplement can have beneficial effects on bone health, muscle health, and metabolic health in postmenopausal women, this intervention could be recommended in the prevention of osteoporosis and associated musculoskeletal and metabolic conditions.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

TRIPLE

Enrollment

160

Conditions

Postmenopausal Osteopenia Bone Loss, Age Related Age-Related Sarcopenia Glucose Metabolism Disorders Age-related Cognitive Decline

Interventions

Pendulum WBF-038DIETARY_SUPPLEMENT

All bacteria contained in Pendulum WBF-038 are commensal organisms that have been repeatedly documented to inhabit the human gastrointestinal tract under normal circumstances. Pendulum's WBF-038 is a proprietary formulation of the following strains: Akkermansia muciniphila, Clostridium butyricum, Clostridium beijerinckii, Anaerobutyricum hallii, Bifidobacterium infantis, plus chicory inulin and magnesium stearate. The organisms were grown under controlled conditions consistent with Good Manufacturing Practices (GMP) and employ no animal-derived products. All ingredients utilized during manufacturing were food grade and qualified as generally recognized as safe (GRAS). The product is provided as acid-resistant capsules in bottles that are to be stored refrigerated at 4℃.

Pendulum PlaceboDIETARY_SUPPLEMENT

Pendulum placebo capsules containing magnesium stearate

Eligibility

Sex: FEMALEMin age: 40 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Postmenopausal women, 40-65 years old * Caucasian (due to significant differences in BMD and bone remodelling between ethnicities) * At least one year since final menses * Signed informed consent * Up to date Covid 19 vaccination status * Able to walk without the use of an aid * Stated availability throughout the entire study period * Mental capacity to understand and willingness to fulfil all the details of the protocol * Residing in Melbourne, Victoria, Australia Exclusion Criteria: * Diagnosis of osteoporosis * T-score of -2.5 or less at the femoral neck or lumbar spine (L1-L4) on the DXA scan at screening visit * HbA1c ≥6.5% at screening visit * Blood pressure at screening visit of systolic \>180 mmHg and/or diastolic \>120 mmHg * Untreated hyperthyroidism * Rheumatoid arthritis * Diagnosed with a disease-causing secondary osteoporosis or malabsorption: chronic obstructive pulmonary disease, inflammatory bowel disease, celiac disease, type 1/type 2 diabetes, or chronic liver disease * Bariatric surgery * Recently diagnosed malignancy (within the last 5 years) * Current or recent oral corticosteroid use (any dose within the last 3 months, or 5mg of Prednisolone (or equivalent) or a higher daily dose for 14 days or more 3-12 months prior to screening) * Use of antiresorptive therapy, including systemic hormone replacement therapy, bisphosphonates, strontium ranelate (current or during the last 3 years) * Use of teriparatide (current or during the last 3 years) * Participation in other clinical intervention trials * Antibiotics treatment 2 months prior to inclusion * Unwilling to cease taking other probiotic or prebiotic supplements (current use)

Locations (1)

Australian Catholic University

Melbourne, Victoria, Australia

Outcomes

Primary Outcomes

Total volumetric bone mineral density of the distal tibia

Percentage change in total volumetric bone density measured using high resolution peripheral quantitative computed tomography (HR-pQCT) of the distal tibia.

Time frame: 12 months

Secondary Outcomes

Bone mineral density of the lumbar spine

Relative change in lumbar spine (L1-L4) bone mineral density (BMD) measured using dual energy X-ray absorptiometry (DXA)

Time frame: 12 months

Bone mineral density of the hip

Relative change in total hip BMD measured using DXA

Time frame: 12 months

Tibia and radius trabecular bone volume

Relative change in tibia and radius trabecular bone volume fraction measured using HR-pQCT

Time frame: 12 months

Tibia and radius cortical area

Relative change in tibia and radius cortical area measured using HR-pQCT

Time frame: 12 months

Tibia and radius cortical volumetric bone mineral density

Relative change in tibia and radius cortical volumetric BMD measured using HR-pQCT

Time frame: 12 months

Total volumetric bone mineral density of the distal radius

Relative change in total volumetric BMD of the distal radius measured using HRpQCT

Time frame: 12 months

Serum C-terminal cross-linking telopeptide of type I collagen (ßCTX-I) - bone turnover marker

Data from ClinicalTrials.gov

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Relative change in ßCTX-I in serum

Time frame: 6 months and 12 months

Serum procollagen type 1 N-terminal propeptide (P1NP) - bone turnover marker

Relative change in P1NP levels in serum

Time frame: 6 months and 12 months

Serum osteocalcin (OC) - bone turnover marker

Relative change in OC in serum

Time frame: 6 months and 12 months

Short-chain fatty acids (SCFAs)

Relative change in SCFA levels (including butyrate) in stool

Time frame: 6 months, 12 months, and 2 weeks post intervention

16s rRNA genetic sequencing of the gut microbiota

Relative change in species-level gut microbiota composition in stool using 16s rRNA sequencing

Time frame: 6 months, 12 months, and 2 weeks post intervention

Fasting blood glucose

Relative change in fasted blood glucose levels in circulating blood

Time frame: 6 months and 12 months

Glycated haemoglobin (HbA1c)

Relative change in HbA1c levels in circulating blood

Time frame: 6 months and 12 months

Lower leg muscle area

Relative change in lower leg muscle area measured using HR-pQCT

Time frame: 12 months

Lean body mass

Relative change in appendicular lean body mass measured using DXA

Time frame: 12 months

Grip strength

Relative change in left and right hand grip strength measured using a hand dynamometer

Time frame: 6 months and 12 months

High-sensitivity C-reactive protein (hs-CRP)

Relative change in hs-CRP levels in serum

Time frame: 6 months and 12 months

Regulatory T lymphocytes (Tregs)

Relative change in circulating number of Tregs in blood

Time frame: 12 months

Oral glucose tolerance test (OGTT)

Relative change in oral glucose tolerance in circulating blood

Time frame: 6 months and 12 months

Muscle tissue glycogen content

Relative change in muscle tissue glycogen content obtained from a muscle biopsy

Time frame: 6 months and 12 months

Muscle tissue triglyceride content

Relative change in muscle tissue triglyceride content obtained from a muscle biopsy

Time frame: 6 months and 12 months

Muscle tissue type 1 fibre composition

Relative change in muscle tissue type 1 fibre proportion obtained from a muscle biopsy

Time frame: 6 months and 12 months

Lipocalin2

Relative change in Lipocalin2 (intestinal inflammation) in stool

Time frame: 6 months, 12 months, and 2 weeks post intervention

Cogstate One back Test Cognitive performance test

Relative change in speed of performance and number of errors in the One Back Test using the Cogstate cognitive assessment tool. Lower score = better performance

Time frame: 6 months and 12 months

Cogstate Groton Maze Learning Test Cognitive performance test

Relative change in number of errors in the Groton Maze Learning Test using the Cogstate cognitive assessment tool. Lower score = better performance

Time frame: 6 months and 12 months

Cogstate Continuous Paired Associate Learning Test Cognitive performance test

Relative change in accuracy of performance and number of errors in the Continuous Paired Associate Learning Test using the Cogstate cognitive assessment tool. Lower score = better performance

Time frame: 6 months and 12 months

Cogstate Social Emotional Cognition Test Cognitive performance test

Relative change in accuracy of performance in the Social Emotional Cognition Test using the Cogstate cognitive assessment tool. Higher score = better performance

Time frame: 6 months and 12 months

Depression, Anxiety and Stress Scale 21

Relative change in depression, anxiety and stress measured using the Depression Anxiety and Stress Scale 21 (DASS-21) questionnaire. The DASS-21 has a minimum score of 0 and a maximum score of 63 with higher scores indicating a worse outcome.

Time frame: 6 months and 12 months

Gastrointestinal Symptom Rating Scale

Relative change in gastrointestinal symptoms measured using the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. The GSRS has a minimum score of 5 and a maximum score of 45 with higher scores indicating a worse outcome.

Time frame: 6 months and 12 months

Plasma glucagon-like peptide 1

Relative change in gut hormone glucagon-like peptide 1 \[GLP-1\] in plasma

Time frame: 6 months and 12 months

Plasma peptide tyrosine-tyrosine

Relative change in gut hormone peptide tyrosine-tyrosine \[PYY\] in plasma

Time frame: 6 months and 12 months

Plasma adiponectin

Relative change adiponectin in plasma

Time frame: 6 months and 12 months

EuroQol Five Dimensions Quality of life Medical Outcome Survey

Relative change in quality of life measured using the EuroQol Five Dimensions (EQ-5D) questionnaire. The EQ-5D has a minimum score of Level 1 and a maximum score of Level 5 with higher levels indicating a worse outcome

Time frame: 6 months and 12 months

Social Interaction Anxiety Scale

Relative change in social anxiety measured using the Social Interaction Anxiety Scale (SIAS) questionnaire. The SIAS has a minimum score of 0 and a maximum score of 80 with higher scores indicating a worse outcome.

Time frame: 6 months and 12 months

The Warwick-Edinburgh Mental Wellbeing Scale

Relative change in mental wellbeing measured using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) questionnaire. The WEMWBS has a minimum score of 14 and a maximum score of 70 with higher scores indicating a better outcome.

Time frame: 6 months and 12 months

Continuous blood glucose level monitoring for 10 days

Relative change in blood glucose (area under the curve) over 10 days measured using a continuous glucose monitoring device

Time frame: 6 months and 12 months

Fasting blood insulin

Relative change in fasted blood insulin levels in circulating blood

Time frame: 6 months and 12 months

Fat mass

Relative change in total body fat mass measured using DXA

Time frame: 12 months

Blood metabolomics

Relative change in blood metabolites using liquid chromatography-mass spectrometry

Time frame: 12 months

Office blood pressure

Relative change in Systolic and Diastolic blood pressure measured using a sphygmomanometer

Time frame: 6 months and 12 months

The Visual Analogue Scale Pain Intensity

Relative change in current pain intensity measured using a visual analogue scale (VAS) pain intensity scale. The VAS has a minimum score of 0 and a maximum score of 10 with higher scores indicating a worse outcome.

Time frame: 6 months and 12 months

Calprotectin

Relative change in calprotectin (intestinal inflammation) in stool

Time frame: 6 months, 12 months, and 2 weeks post intervention

Muscle mass

Relative change in total body muscle mass measured using DXA

Time frame: 12 months