Intervention studies
Small studies in adults deprived of dietary copper documented adverse changes in blood cholesterol, including increased total and LDL cholesterol concentrations and decreased HDL cholesterol concentrations (107), but these outcomes were not confirmed in other studies (108). For example, in one recent study, copper supplementation of 2 to 3 mg/day for 4 to 8 weeks did not result in clinically significant changes in blood cholesterol levels (81, 109, 110). Additionally, 8 mg/day of copper for six months had no effect on blood cholesterol levels (111). Interpretation of these outcomes is, however, challenging since the copper status of participants was presumably not well defined. Additional research failed to link increased copper intake to elevated oxidative stress. In a multi-center, placebo-controlled clinical trial, copper supplementation of 3 or 6 mg/day for six weeks did not result in increased susceptibility of LDL to oxidation by copper (112). Moreover, supplementation with 3 or 6 mg/day of copper did not increase oxidative damage to red blood cells (113). Collectively, these studies indicated that copper intakes several times above the RDA do not increase oxidative stress, at least as measured by these assays in these populations.
Summary: Copper and cardiovascular disease
Although free copper and CP can promote LDL oxidation in the laboratory, there is little evidence that high dietary copper increases oxidative stress in the human body. Increased serum copper levels have been associated with increased CVD risk, as outlined above, but the significance of these findings is unclear due to the complex association among serum copper, CP, and inflammatory mediators. Clarification of the relationships of copper intake, copper nutritional status, CP levels, and CVD risk thus requires further research.
Immune system function
Copper is known to play several important roles in the development and maintenance of immune system function, including innate and adaptive immunity (reviewed in 114). Neutropenia is a clinical sign of copper deficiency in humans. Adverse effects of insufficient copper on immune system function appear most pronounced in infants. For example, infants with Menkes disease, a genetic copper-deficiency disorder, suffer from frequent and severe infections (115, 116). Moreover, in a study of 11 malnourished infants with evidence of copper deficiency, the ability of white blood cells to engulf pathogens increased significantly after one month of copper supplementation (117). Moreover, 11 men on a low-copper diet (0.66 mg/day of copper for 24 days and 0.38 mg/day for another 40 days) showed an impaired monocyte proliferative response in an ex vivo immune challenge assay (118). Mechanistic studies also support a role for copper in the innate immune response to bacterial and viral infections (reviewed in 119, 120). Severe copper deficiency thus has adverse effects on immune system function; however, whether marginal copper insufficiency impairs immunity in humans has not been established.
Osteoporosis
Progressive decrease of bone mineral density (BMD) is commonly observed in the elderly, frequently leading to development of osteopenia (pre-osteoporosis) and osteoporosis. Women are more often affected by osteoporosis than men, (e.g., prevalence ratio is 5:1 in non-Hispanic whites) (121), primarily due to the postmenopausal reduction in the production of estrogen, which is essential for maintaining strength of muscle, bone, and connective tissue (122). Osteoporosis is associated with an increased risk of falls, bone fracture, and mortality in individuals over 65 years of age (123).
Osteoporosis has been reported in infants with severe copper deficiency (124, 125), but how copper depletion affects bone and connective tissue health in adults is less certain. One recent investigation documented bone resorption (breakdown) in 11 healthy adult males consuming marginal copper for six weeks (0.7 mg/day) (126). Also, supplementation of 3 to 6 mg/day of copper for six weeks had no effect on biochemical markers of bone resorption or bone formation in two studies of healthy adult men and women (127, 128). An effect of copper deficiency on bone integrity seems likely, since a copper-dependent enzyme, lysyl oxidase (LOX), is required for the maturation (cross-linking) of collagen, a key element in the organic matrix of bone. In individuals with marginal copper intake and less efficient copper absorption, such as the elderly, it seems plausible that LOX activity is decreased, possibly increasing risk for bone and connective tissue effects.
Observational studies
Collectively, research examining the role of copper nutritional status in age-related osteoporosis is limited. An early study found that serum copper levels in 46 elderly patients with hip fractures were significantly lower than those of age-matched controls (129). Another study, however, found no differences in serum copper levels among postmenopausal women with normal BMD (N=40), osteopenia (N=40), or osteoporosis (N=40) (130). A cross-sectional study showed that blood copper concentrations were lower than the normal reference range in postmenopausal women with osteopenia (N=28) and osteoporosis (N=23) (131). In another cross-sectional study in 728 postmenopausal women, 491 of which had confirmed osteoporosis, lower serum copper concentrations were associated with osteoporosis in the younger women (ages 40-59 years) but not the older women (ages 60-80 years) (132). Furthermore, in a national survey in the US, including 8,224 adults (compiling data from NHANES 2007-2010, 2013-2014, and 2017-2018), higher daily copper intakes (from diet and supplements) were associated with higher BMD at the femur and lumbar spine and a lower risk of osteoporosis (133).
Intervention studies
Limited studies of copper supplementation and bone health outcomes have been undertaken. A small study in perimenopausal women, who consumed ~1 mg of dietary copper daily, reported decreased loss of BMD from the lumbar spine after copper supplementation of 3 mg/day for two years (134). Additionally, a two-year, double-blind, placebo-controlled trial in 59 postmenopausal women found that daily intake of supplemental calcium plus trace minerals, including 2.5 mg of copper, resulted in maintenance of spinal BMD. Supplemental calcium or trace minerals, alone, were not as effective at preventing loss of bone density (135). Another randomized, double-blind, placebo-controlled study in 224 healthy, postmenopausal women ages 51 to 80 years, found daily supplementation with 600 mg of calcium, 2 mg of copper, and 12 mg of zinc for two years decreased whole-body BMD compared to supplemental calcium alone. Another trial showed that BMD was reduced in subjects with dietary copper intakes below the RDA (0.9 mg/day), but copper supplementation did not prevent the progressive loss of BMD as well as a calcium regimen alone (136). Finally, several studies have suggested that tooth loss might be related to defects in the maintenance of BMD (137, 138). When compared with 20 healthy-matched controls, 50 patients (mean age, 47.5 years) with low spinal BMD and advanced tooth wear were found to have significantly lower copper content in tooth enamel. However, despite evidence of bone demineralization, serum copper levels in this population were similar to those of the healthy group (139). In sum, additional research is required to draw meaningful conclusions regarding the effects of marginal copper depletion and copper supplementation on bone metabolism and risk for developing age-related osteoporosis.
