The Efficacy and Safety of Multiple Dose Regimens of Kudzu (Pueraria lobata) Root Extract on Bone and Cartilage Turnover and Menopausal Symptoms

Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata, Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear.Purpose: This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms.Materials and Methods: Fifty postmenopausal women were randomized equally into five different dose regimen groups of Kudzu root extract in a four-week, parallel group, open-label, single-center, exploratory study design. Biomarkers CTX-I and CTX-II reflecting bone and cartilage degradation, respectively, were assessed in blood samples and 24-h urine samples. Change from baseline in the Menopause Rating Scale (MRS) and subscales was evaluated. Safety endpoints were frequency of adverse events, changes in hematology and safety chemistry data, vital signs and electrocardiogram.Results: Fifty women (Age 54.2 years, SD: 2.9) were randomized. After 4 weeks of treatment, biomarkers of bone resorption and cartilage degradation were statistically significantly reduced from baseline levels in the group receiving two capsules three times a day, serum/urine CTX-I (−18.4%, 95% CI: −8.1 to −27.5, p = 0.001/−34.2%, 95% CI: −21.6 to −44.7, p < 0.0001), urine CTX-II (−17.4% 95% CI: −2.5 to −30.0, p = 0.02). The observed effects were consistent across study groups but appeared to favour three times daily dosing. Four weeks of treatment led to statistically significant reductions in the MRS Total Score (p < 0.0001–0.03) in four out of five treatment groups. Kudzu root extract was well tolerated in all dose regimens, and no serious adverse events were reported.Conclusion: The results indicate that Kudzu extract may possess beneficial effects on bone and cartilage health and may be a promising natural alternative to existing treatments for menopausal symptoms. Kudzu root extract was well tolerated for short-term treatment of mild to severe menopausal symptoms in women in all tested doses and dose frequencies.

Effect of GreenshellTM mussel on osteoarthritis biomarkers and inflammation in healthy postmenopausal women: a study protocol for a randomized double-blind placebo-controlled trial

Background New Zealand Greenshell™ mussels (GSM; Perna canaliculus) have recently been shown to decrease cartilage degradation in a rat model of induced metabolic osteoarthritis (MetOA). However, this effect has not been investigated in human subjects. This study aims to determine the effect of GSM powder on biomarkers of cartilage metabolism, bone resorption, and inflammation in New Zealand healthy overweight/obese postmenopausal women who are at early stage or at high risk of OA. Method Fifty overweight or obese (BMI 25–35 kg/m2) postmenopausal women (aged 55–75 years) will be recruited by advertisement. Participants will be randomized based on a double-blind randomization schedule and stratified randomization based on BMI and age distribution. The participant will be assigned with a 1:1 allocation ratio to receive 3 g/d whole meat GSM powder or placebo (sunflower seed protein) for 12 weeks. Data on socio-demographics, physical activity, and dietary intake will be collected for each subject. Cartilage turnover biomarkers [(C-telopeptide of type II collagen (CTX-II), C-propeptide of type II procollagen (CPII), Cartilage oligomeric matrix protein (COMP)], and bone resorption marker (CTX-I) will be measured in blood and urine samples. Inflammatory status (hs-CRP and cytokine panel) will be assessed and iron status will be measured. Body composition including fat mass (FM), lean mass (LM), and fat percentage will be measured using dual-energy X-ray absorptiometry (DXA). Joint pain and knee function will be assessed using a 100-mm visual analog scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, respectively. Discussion This trial will be the first to explore the effects of whole meat GSM powder on cartilage turnover, bone resorption, and inflammation biomarkers in overweight/obese postmenopausal women. The results from this trial will provide evidence on the efficacy of GSM in the prevention of OA. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000413921p. Registration on 27 March 2020.

Effect of GreenshellTM Mussel on the Osteoarthritis Biomarkers and Inflammation in Healthy Postmenopausal Women: A Study Protocol for Randomized Double ‑ Blind Placebo ‑ Controlled Trial

Background: New Zealand Greenshell™ mussels (GSM; Perna canaliculus) has recently been shown to decrease cartilage degradation in a rat model of induced metabolic osteoarthritis (MetOA). However, this effect has not been investigated in human subjects. This study aims to determine the effect of GSM powder on biomarkers of cartilage metabolism, bone resorption, and inflammation in New Zealand healthy overweight/obese postmenopausal women. Method: Fifty overweight or obese (BMI 25-35 kg/m2) postmenopausal women (aged 55-75 years) will be recruited. They will be randomly assigned to receive 3 g/d whole meat GSM powder or placebo (sunflower seed protein) for 12 weeks. Data on socio-demographics, physical activity and dietary intake will be collected for each subject. Cartilage turnover biomarkers [(C-telopeptide of type II collagen (CTX-II), C-propeptide of type II procollagen (CPII), Cartilage oligomeric matrix protein (COMP)], and bone resorption marker (CTX-I) will be measured in blood and urine samples. Inflammatory status (hs-CRP and cytokine panel) will be assessed and iron status will be measured. Body composition including fat mass (FM), lean mass (LM) and fat percentage will be measured using dual-energy X-ray absorptiometry (DXA). Joint pain and knee function will be assessed using a 100 mm Visual Analogue Scale (VAS) and the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire, respectively.Discussion: This trial will be the first to explore the effects of whole meat GSM powder on cartilage turnover, bone resorption and inflammation biomarkers in overweight/obese postmenopausal women. The results from this trial will provide evidence on the efficacy of GSM in prevention of OA. Trial registration: The study was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) with the number ACTRN12620000413921p. Registration date: 27/03/2020. https://www.anzctr.org.au/Trial/Update/Step1_Update.aspx?id=379291

Low dietary silicon supplementation may not affect bone and cartilage in mature, sedentary horses

As osteoarthritis is a major cause of lameness in horses in the United States, improving collagen health prior to onset and increasing collagen turnover within affected joints could improve health- and welfare-related outcomes. Through its positive effects on bone mineral content and density and its role in increasing collagen synthesis, silicon (Si) may slow the development and progression of osteoarthritis, thereby reducing lameness. This study evaluated the hypothesis that Si supplementation would increase cartilage turnover through increased collagen degradation and formation markers, as well as bone formation markers, resulting in reduced lameness severity when compared with controls. Ten mature Standardbred geldings were assigned to either a Si-treated (SIL) or control (CON) group and group-housed on pasture for 84 d. Horses were individually fed to ensure no cross-contamination of Si other than what was present in the environment. For the duration of the study, SIL horses received a Si–collagen supplement at the rate of 0.3 g supplement/(100 kg body weight day). Serum samples were taken weekly for osteocalcin, and plasma samples were taken on days 0, 42, and 84 for plasma minerals. On days 0, 42, and 84, subjective and objective lameness exams were performed, and radiographs and synovial fluid samples were taken from reference and osteoarthritic joints. Plasma minerals were similar in both groups and were lower on day 84 than on day 0 (P < 0.05). Si supplementation, fed at the manufacturer’s recommended rate, did not improve lameness or radiographs when compared with controls, and supplemented horses did not show greater collagen degradation and/or synthesis markers in synovial fluid than controls, indicating that cartilage turnover remained unaffected. However, a minimum beneficial threshold and range for Si supplementation standardized to body weight need to be established.

The Anti-ADAMTS-5 Nanobody® M6495 Protects Cartilage Degradation Ex Vivo

Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody® (M6495) on cartilage turnover ex vivo. Bovine cartilage (BEX, n = 4), human osteoarthritic - (HEX, n = 8) and healthy—cartilage (hHEX, n = 1) explants and bovine synovium and cartilage were cultured up to 21 days in medium alone (w/o), with pro-inflammatory cytokines (oncostatin M (10 ng/mL) + TNFα (20 ng/mL) (O + T), IL-1α (10 ng/mL) or oncostatin M (50 ng/mL) + IL-1β (10 ng/mL)) with or without M6495 (1000−0.46 nM). Cartilage turnover was assessed in conditioned medium by GAG (glycosaminoglycan) and biomarkers of ADAMTS-5 driven aggrecan degradation (huARGS and exAGNxI) and type II collagen degradation (C2M) and formation (PRO-C2). HuARGS, exAGNxI and GAG peaked within the first culture week in pro-inflammatory stimulated explants. C2M peaked from day 14 by O + T and day 21 in co-culture experiments. M6495 dose dependently decreased huARGS, exAGNxI and GAG after pro-inflammatory stimulation. In HEX C2M was dose-dependently reduced by M6495. M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures.

An Assessment of Hip Strength, Patient Reported Outcomes, and Plasma Inflammatory Biomarkers After Surgical Correction for Symptomatic Femoroacetabular Impingement

Objectives: Patients with Femoroacetabular impingement (FAI) have been shown to have elevated circulating biomarkers of inflammation and cartilage catabolism, but little is known about whether corrective surgical intervention improves objective measures of hip strength and inflammation. This study measured several variables including pain, function, quality of life, symptoms, hip strength, and inflammatory and cartilage biomarkers in a cohort of subjects undergoing FAI surgery and postoperative (postop) rehabilitation. We hypothesized that surgical FAI repair and completion of a postop rehabilitation program will significantly improve patient reported outcomes (PROs), increase hip flexion and abduction strength measures, and decrease biomarkers of inflammation and cartilage degradation. Methods: This study was approved by the University of Michigan Medical School IRB (HUM00055335). Male and female patients aged 16-40 years of age, with symptomatic FAI diagnosed by concordant history, physical examination, and imaging findings were eligible for inclusion. Subjects who have undergone previous hip surgery, have a global overcoverage deformity, dysplasia, or degenerative chondral changes greater than Tonnis grade I were excluded. A single, fellowship trained, sports medicine orthopaedic surgeon performed all surgical procedures, and patients underwent a standardized postop rehabilitation program. HOOS questionnaires were assessed at each subject’s preoperative visit (preop), and at 2, 14, 26, and 52 weeks postop. Hip flexion, abduction, and extension were measured at each time point using a BioDex isokinetic dynamometer. High sensitivity C-reactive protein (HS-CRP) and cartilage oligomeric matrix protein (COMP) were measured in plasma using ELISAs. Differences between preop and postop time points were assessed using a mixed-effects model, and data are reported as mean±95% CI. Results: A total of 11 males and 6 females completed the study. Mean age of subjects was 25.2±3.8 years (range 16.0-38.0 years) and BMI of 24.2±2.0 kg/m2 (range 18.1-33.6 kg/m2). For most HOOS subscales, there was a decrease in score at 2 weeks postop, and by 14 weeks activities of daily living (ADL) improved by 18%, pain by 34%, quality of life by 69%, sport and recreation by 36%, and symptoms by 28% compared to preop values (Figure 1A-E). These improvements in HOOS subscales persisted for the duration of the study period (Figure 1A-E). No differences in hip flexion strength were observed, while extension was 20% and 31% significantly higher than preop values at 26 and 52 weeks, and for abduction patients were 34% stronger than preop values at 52 weeks. No differences in HS-CRP or COMP were observed (Figure 1F-J). Conclusion: In support of our hypothesis, we observed significant improvements in PROs of hip function, although changes in PROs preceded improvements in objective measures of hip extension and abduction strength. Despite improvements in other planes, no changes in hip flexion were observed. Plasma biomarkers of hip inflammation and cartilage turnover were not reduced by surgical intervention and rehabilitation. FAI surgery and postop rehabilitation is effective at treating pain, and improving patient reported quality of life and symptoms, with modest improvements in hip strength. However, the surgical correction of pathological hip anatomy and improvements in hip strength did not lead to significant differences in markers of inflammation or cartilage turnover.

OP0189 ASSESSMENT OF CARTILAGE DEGRADATION AND PROTECTIVE MARKERS IN SYNOVIAL FLUID FROM OSTEOARTHRITIS PATIENTS BEFORE AND AFTER CYCLES OF INTRA-ARTICULAR INJECTIONS WITH SPRIFERMIN

Background:It is challenging to monitor treatment effects after intra-articular (IA) injection with tissue modifying drugs. Assessment of biomarker levels in synovial fluid may be one solution to the challenge. Sprifermin is a truncated form of fibroblast growth factor (FGF) 18 known to induce chondrocyte proliferation and type II collagen formation [1,2]. Data from preclinical investigations show that cartilage formation happens in different phases after therapy with sprifermin, starting with a phase of cartilage degradation during the induction of proliferation of chondrocytes followed by a phase of cartilage formation/production of extracellular matrix.Objectives:The aim was to investigate the effect of IA administrated sprifermin on cartilage turnover activity as compared to placebo in the injected joint by measurement of markers using longitudinal synovial fluid samples of patients participating in the FORWARD study.Methods:Each included patient had baseline and at least one FU sample available. Synovial fluid (SF) from participants receiving injections at three consecutive weeks in six month intervals through to week (wk) 80 (fig.A) available from the phase II clinical trial evaluating the efficacy and safety of intraarticularly delivered sprifermin [3] were selected for the investigations. Biochemical markers were measured in available SF samples of the placebo (containing saline IA, n=38) and the highest sprifermin dose group (100 mcg/IAx4, n=59). Samples were pretreated with ultrasound and centrifugation to decrease viscosity. Markers measured were PRO-C2 (type II collagen formation), huARGS (aggrecan degradation), and FBN-C (fibronectin). Markers are technically validated for synovial fluid measurement. Data were individually normalized to baseline to investigate the median proportional change over time.Results:Baseline mean (SD) levels of the markers in SF at BL were: PRO-C2, 21.4 (13.6) ng/mL, huARGS, 1117 (516) pM and FBN-C, 2556 (1959) ng/mL. PRO-C2 was initially decreased (from BL to wk 2) after injection with sprifermin; however, the level was increased at the beginning of each new injection cycle followed by a decrease after injection of sprifermin (Fig.B). Overall synovial PRO-C2 levels increased over time in therapy with sprifermin, while no change was observed for the placebo arm. huARGS showed a similar pattern as PRO-C2 – there was an overall increase in ARGS over time in the sprifermin group (fig.C). Interestingly ARGS continuously decreased over time in the placebo group. FBN-C is continuously increased after injection’s cycles, whereas no effect was seen in the placebo group (fig.D).Conclusion:Confirmatory of the preclinical investigations a biphasic response on cartilage turnover after injection with sprifermin was observed. Biochemical indications of cartilage formation and chondrocyte proliferation was only modulated in the sprifermin group, and cartilage degradation (ARGS) was temporal induced and reduced by sprifermin and placebo injections, respectively.References:[1]Gigout A, et al. “Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix”. Osteoarthr Cartil. 2017;25.[2]Reker D, et al. “Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo”. J Transl Med. 2017;15.[3]Hochberg MC, et al. “Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With Osteoarthritis”. JAMA. 2019; Oct 8;322(14).Disclosure of Interests:Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Angela Manginelli Employee of: Merck KGaA, Flavie Moreau Employee of: Merck KGaA, Yi He Employee of: YH is a full time employee of Nordic Bioscience A/S, Yunyun Luo Employee of: Nordic Bioscience A/S, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee of Nordic Bioscience., Asger Reinstrup Bihlet Shareholder of: Nordic Bioscience A/S., Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Hans Gühring Employee of: Merck KGaA, Christoph Ladel Employee of: Merck KGaA

Effects of a multinutrient-fortified milk drink combined with exercise on functional performance, muscle strength, body composition, inflammation, and oxidative stress in middle-aged women: a 4-month, double-blind, placebo-controlled, randomized trial

ABSTRACT Background Multinutrient protein-enriched supplements are promoted to augment the effects of exercise on muscle mass and strength, but their effectiveness in middle-aged women, or whether there are any additional benefits to physical function, remains uncertain. Objectives We aimed to evaluate whether a multinutrient-fortified milk drink (MFMD) could enhance the effects of exercise on functional muscle power (stair climbing) in middle-aged women. Secondary aims were to evaluate the intervention effects on physical function, muscle strength, lean mass (LM), fat mass (FM), bone mineral content (BMC), muscle cross-sectional area (CSA), muscle density, balance, flexibility, aerobic fitness, inflammation, oxidative stress, bone and cartilage turnover, blood pressure, and blood lipids. Methods In this 4-mo, double-blind, placebo-controlled, randomized trial, 244 women (45–65 y) participated in a multimodal resistance-type exercise program 3 d/wk, with random allocation to a twice-daily MFMD containing added protein, vitamin D, calcium, milk fat globule membrane (phospholipids and other bioactives), and other micronutrients (Ex + MFMD, n = 123) or an energy-matched placebo (Ex + placebo, n = 121). Results A total of 216 women (89%) completed the study. After 4 mo, both groups experienced similar 3.6%–4.3% improvements in the primary outcomes of fast-pace 5- and 10-step stair ascent power. In contrast, Ex + MFMD experienced greater improvements in 5-step regular-pace stair descent time [net difference (95% CI): −0.09 s (−0.18, 0.00 s), P = 0.045], countermovement jump height [0.5 cm (0.04, 1.0 cm), P = 0.038], total body LM [0.3 kg (0.04, 0.60 kg), P = 0.020], FM [−0.6 kg (−1.0, −0.2 kg), P = 0.004], BMC [0.4% (0.1%, 0.6%), P = 0.020], muscle CSA [thigh: 1.8% (0.6%, 2.9%), P = 0.003; lower leg: 0.9% (0.3%, 1.6%), P = 0.005], balance eyes closed [3.3 s (1.1, 5.4 s), P = 0.005], 2-min step performance [8 steps (3, 12 steps), P = 0.003], and sit-and-reach flexibility [1.4 cm (0.6, 2.2 cm), P = 0.026]. MFMD did not enhance the effects of exercise on any measures of muscle strength, gait speed, dynamic balance, reaction time, or blood lipids, and there was no effect of either intervention on blood pressure, markers of inflammation, or cartilage turnover. Ex + placebo had a greater improvement in the oxidative stress marker protein carbonyls (P < 0.01). Conclusions In middle-aged women, daily consumption of an MFMD did not enhance the effects of a multimodal exercise program on the primary outcome of stair climbing ascent power, but did elicit greater improvements in multiple secondary outcomes including various other measures of functional performance, LM, muscle size, FM, balance, aerobic capacity, flexibility, and bone metabolism. This trial was registered at www.anzctr.org.au as ACTRN12617000383369.