Title: The Effect of Selenium Supplementation on Musculoskeletal Health in Older Women
Funder: Department of Health and Social Care

Abstract: About 30% of women over age 65 have osteopenia (bone mineral density (BMD) T-score -1.0 to -2.5). They are at increased risk of fracture and likely to develop osteoporosis, but their BMD is not low enough for osteoporosis treatment such as bisphosphonates. Previously these women may have been offered hormone replacement therapy (HRT), but adverse events have reduced HRT use, so there is a large unmet clinical need. Selenium is a chemical element present in several human enzymes, including regulators of thyroid hormone synthesis. Selenoproteins are anti-inflammatory and antioxidant; they reduce interleukin-6 and reactive oxygen species which are potent stimuli for bone resorption (1-3). We have recently published evidence that plasma selenium is associated with BMD and bone turnover in a European population-based sample of older women (4). This provides proof of concept, but not causation or efficacy. If the association is causative, selenium supplementation may be beneficial to bone health, particularly in the UK where mean dietary selenium intake is below recommended levels and has decreased in recent years. We hypothesise that selenium supplementation will decrease bone turnover and increase BMD, and it may do this by reducing reactive oxygen species. The aims of this study are to determine if selenium supplementation in osteopenic postmenopausal women decreases bone turnover, is safe and well-tolerated, improves muscle function and decreases markers of oxidative stress and inflammation. It will also determine the best dose to take forward into a longer study of BMD response. We will evaluate two doses of selenium (50 and 200mcg) vs placebo over six months in a randomised, double-blind, placebo controlled trial. Participants will be osteopenic postmenopausal women. The primary endpoint will be difference in urinary N-telopeptide of type I collagen (NTX), a biochemical marker of bone resorption. Mean NTX/Cr between the groups will be compared with analysis of covariance (ANCOVA) adjusting for baseline NTX/Cr. Bone turnover markers change much more rapidly than BMD, so we can determine quickly and cost-efficiently whether selenium is likely to be beneficial. There is substantial existing data showing the relationship between reduction in bone resorption, increase in BMD and decrease in fracture risk with other osteoporosis treatments. The minimum sample size required to detect a clinically significant decrease in NTX (20%) is 21 women per group. We will recruit 33 women with low serum selenium per group, to allow for drop-out, group imbalance and secondary endpoint analysis (80% of UK women have low serum selenium, so we expect to recruit a total of 120). If selenium supplementation does decrease bone resorption, we will immediately seek funding for a longer trial with BMD as the primary endpoint. There is already a UK licensed selenium preparation, so if a BMD trial is positive, selenium supplementation for osteopenic women could be in clinical practice within the next five years.

Lay abstract: This research aims to determine whether selenium supplements improve bone and muscle health in older women at risk of osteoporosis (low bone density or weak bones) and fracture (broken bones). Osteoporosis is a major public health problem. One in two women and one in five men over age 50 will have a fracture. Fractures cause pain, disability and reduce life-expectancy. Women with below-average bone density might have previously taken hormone replacement (HRT) to prevent osteoporosis, but HRT is much less used now due to side effects. Therefore there is a need for safe, effective and inexpensive interventions for women at risk of osteoporosis. Selenium is a chemical nutrient present in several human proteins, including anti-oxidants. Anti-oxidants may protect against ageing of tissues, including bone, by mopping up damaging molecules (sometimes called ‘free radicals’). Selenium is present in soil, and so is obtained from many foods. However, soil selenium levels are low in Europe, and dietary intake in the UK is below recommended levels. We previously found that women with higher blood selenium levels have stronger bones, but this doesn’t prove that giving selenium will improve bone strength. We propose a randomised controlled trial to compare selenium supplements with a placebo (dummy treatment) in women with below-average bone density. We will give selenium (at two different doses) or placebo to 120 women for six months and use blood and urine tests to see if giving selenium does have any effect on bone. We will also do muscle function tests and measurements of free radical molecules. The study has been reviewed and is supported by the Sheffield Lay Advisory Panel for Bone Research. The Panel will contribute to the study management and dissemination of the results. The results will presented at national and international conferences and submitted to high impact journals.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL