Nicola M. Lowe

Is there a potential therapeutic value of copper and zinc for osteoporosis

Osteoporosis is almost universal in very old age, and is a major cause of morbidity and mortality in the elderly of both sexes. Bone is lost at a rate of 0.2-0.5 %/year in both men and women after the age of 40-45 years. The causes of age-related changes in bone mass are multifactorial and include genetic predisposition, nutritional factors, endocrine changes, habitual exercise levels and body weight. Bone loss is accelerated to 2-5 % year immediately before and for up to 10 years post-menopause (Heaney, 1986). In women hormone-replacement therapy is effective in reducing the rate of bone loss caused by this peri-menopausal decrease in hormone levels (Smith & Studd, 1993); however, in men and older women (>10 years post-menopause) nutrition plays a key role in the rate of bone loss. One factor contributing to bone loss in the elderly may be a subclinical Zn and/or Cu deficiency, due to a reduced dietary intake of micronutrients and reduced absorption (Thomson & Keelan, 1986). Zn and Cu are essential cofactors for enzymes involved in the synthesis of various bone matrix constituents. Paradoxically, Ca supplementation may accentuate the problem of reduced Zn and Cu levels by impairing the absorption of simultaneously-ingested Zn and the retention of Cu (Snedeker et al. 1982; Grekas et al. 1988). The present paper will review the current literature on the potential benefits of Cu and Zn supplementation in reducing bone loss, and present new information on the effect of Ca supplementation on Zn and Cu status in post-menopausal women with osteoporosis.

Assessment of the Trace Element Status of Individuals and Populations: The Example of Zinc and Copper

This paper describes the proceedings of a workshop that was convened at the 11th International Symposium on Trace Elements in Man and Animals (TEMA-11) symposium to review recent advances concerning the assessment of the trace element status of individuals and populations, using zinc and copper as the primary examples to illustrate basic principles and recent advances in assessment methods. The workshop was initiated with a brief review of the importance of zinc nutriture for human health and a discussion of the likely common occurrence of zinc deficiency worldwide. This overview was followed by presentations on selected issues concerning the assessment of zinc status, with particular attention devoted to dietary assessment techniques, the use of isotopic tracers to assess zinc homeostasis and the relationship of these methods to biochemical indicators of zinc status. Because relatively little information is available on zinc toxicity, the discussion concerning the definition of excess intake of trace elements focused primarily on recent work concerning risk assessment of copper toxicity.

The Relationship between Zinc Intake and Serum/Plasma Zinc Concentration in Children: A Systematic Review and Dose-Response Meta-Analysis

Recommendations for zinc intake during childhood vary widely across Europe. The EURRECA project attempts to consolidate the basis for the definition of micronutrient requirements, taking into account relationships among intake, status and health outcomes, in order to harmonise these recommendations. Data on zinc intake and biomarkers of zinc status reported in randomised controlled trials (RCTs) can provide estimates of dose-response relationships which may be used for underpinning zinc reference values. This systematic review included all RCTs of apparently healthy children aged 1–17 years published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient () was calculated for each individual study and calculated the overall pooled and SE () using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status indicated that a doubling of the zinc intake increased the serum/plasma zinc status by 9%. This evidence can be utilised, together with currently used balance studies and repletion/depletion studies, when setting zinc recommendations as a basis for nutrition policies.

Vitamin D status and markers of bone turnover in Caucasian and South Asian postmenopausal women living in the UK

Suboptimal vitamin D status among the South Asian UK population is widely reported; however, its impact on bone health is unclear. The aim of the present study was to conduct a comparative investigation of vitamin D status in postmenopausal South Asian (SA) and Caucasian (C) women and its relationship to parathyroid hormone (PTH) concentration, biochemical markers of bone turnover and bone quality. A cross-sectional study of community-dwelling women aged 50-66 years was carried out. A total of sixty-six SA women of Pakistani origin and forty-two C women living in the same community were recruited. Fasting blood was taken for the measurement of vitamin D, PTH and biochemical markers of bone turnover, including type-1 collagen beta C-telopeptide (betaCTX), procollagen type-1 amino-terminal propeptide (P1NP), and bone-specific alkaline phosphatase (BAP) activity. Bone quality was assessed using broadband ultrasound attenuation (BUA). Total serum 25-hydroxyvitamin D (25(OH)D) was significantly lower in the SA women than the C women (medians: SA 10.5 v. C 47.1 nmol/l; P < 0.001) This was associated with a significantly elevated serum PTH concentration in the SA group (medians: SA 7.3 v. C 4.5 pmol/l; P < 0.01). BAP activity was also significantly higher in the SA group, indicating elevated osteoblast activity and bone turnover (medians: SA 23.0 v. C 20.0 U/l; P < 0.05). No significant differences were observed between the two groups for P1NP, betaCTX or BUA. Although the SA women had significantly higher serum PTH and lower 25(OH)D concentrations than C women, this was not associated with significantly higher markers of bone resorption, or reduced bone quality in the SA women.

Effect of maximal exercise on the short‐term kinetics of zinc metabolism in sedentary men

Objective: To examine the effect of acute exhaustive exercise versus rest on short-term zinc kinetics in men. Design: Crossover design, wherein all subjects were their own control. Setting: University setting, where subjects were free living. Participants: 12 healthy, sedentary men, 25–35 years of age. Interventions:70Zn was infused 10 min after exercise or at rest. Plasma zinc concentrations were measured at baseline and 2, 5, 10, 15, 30, 45, 60, 75, 90 and 120 min after exercise or rest. Haematocrit was measured before and after exercise to assess changes in plasma volume. Main outcome measurements: Plasma zinc (primary), serum creatine kinase and serum cortisol concentrations (secondary). Results: Plasma zinc concentrations decreased (p<0.05) after exercise, with a mean (SD) nadir of 13.9% (4.1%) observed at 70 min after exercise. There were increases in the size of the rapidly exchangeable plasma zinc pool (Qa; from 3.1 (0.2) to 3.6 (0.2) mg; p<0.05) and the liver zinc pool (Qb; from 10.2 (0.6) to 11.4 (0.8) mg; p = 0.12). Conclusion: Exercise seems to cause a shift of plasma zinc into the interstitial fluid and liver after exercise, which may reflect the acute stress response of strenuous exercise.

Zinc intake, status and indices of cognitive function in adults and children: a systematic review and meta-analysis

In developing countries, deficiencies of micronutrients are thought to have a major impact on child development; however, a consensus on the specific relationship between dietary zinc intake and cognitive function remains elusive. The aim of this systematic review was to examine the relationship between zinc intake, status and indices of cognitive function in children and adults. A systematic literature search was conducted using EMBASE, MEDLINE and Cochrane Library databases from inception to March 2014. Included studies were those that supplied zinc as supplements or measured dietary zinc intake. A meta-analysis of the extracted data was performed where sufficient data were available. Of all of the potentially relevant papers, 18 studies met the inclusion criteria, 12 of which were randomised controlled trials (RCTs; 11 in children and 1 in adults) and 6 were observational studies (2 in children and 4 in adults). Nine of the 18 studies reported a positive association between zinc intake or status with one or more measure of cognitive function. Meta-analysis of data from the adult’s studies was not possible because of limited number of studies. A meta-analysis of data from the six RCTs conducted in children revealed that there was no significant overall effect of zinc intake on any indices of cognitive function: intelligence, standard mean difference of <0.001 (95% confidence interval (CI) –0.12, 0.13) P=0.95; executive function, standard mean difference of 0.08 (95% CI, –0.06, 022) P=0.26; and motor skills standard mean difference of 0.11 (95% CI –0.17, 0.39) P=0.43. Heterogeneity in the study designs was a major limitation, hence only a small number (n=6) of studies could be included in the meta-analyses. Meta-analysis failed to show a significant effect of zinc supplementation on cognitive functioning in children though, taken as a whole, there were some small indicators of improvement on aspects of executive function and motor development following supplementation but high-quality RCTs are necessary to investigate this further.

The relationship between zinc intake and growth in children aged 1–8 years: a systematic review and meta-analysis

Background/objectives:It is estimated that zinc deficiency affects 17% of the worlds population, and because of periods of rapid growth children are at an increased risk of deficiency, which may lead to stunting. This paper presents a systematic review and meta-analysis of the randomised controlled trials (RCTs) that assess zinc intake and growth in children aged 1–8 years. This review is part of a larger systematic review by the European Micronutrient Recommendations Aligned Network of Excellence that aims to harmonise the approach to setting micronutrient requirements for optimal health in European populations (www.eurreca.org).Subject/methods:Searches were performed of literature published up to and including December 2013 using MEDLINE, Embase and the Cochrane Library databases. Included studies were RCTs in apparently healthy child populations aged from 1 to 8 years that supplied zinc supplements either as capsules or as part of a fortified meal. Pooled meta-analyses were performed when appropriate.Results:Nine studies met the inclusion criteria. We found no significant effect of zinc supplementation of between 2 weeks and 12 months duration on weight gain, height for age, weight for age, length for age, weight for height (WHZ) or WHZ scores in children aged 1–8 years.Conclusions:Many of the children in the included studies were already stunted and may have been suffering from multiple micronutrient deficiencies, and therefore zinc supplementation alone may have only a limited effect on growth.

Dantrolene sodium protects against experimental ischemia and reperfusion damage to skeletal muscle

The effect of 4 hours of ischemia followed by reperfusion for 1 hour has been studied in fully anesthetized rabbits. Muscles from the limb subjected to ischemia and reperfusion showed considerable ultrastructural damage, although the distribution of damage between muscles was not uniform (anterior tibialis > soleus > quadriceps). Damage to the muscle was associated with a significant increase in the concentration of some indicators of free radical-mediated processes (thiobarbituric acid-reactive substances and diene conjugates), although others (glutathione and protein sulfhydryl groups) were unchanged. Reperfused muscles also showed considerable changes in their calcium and sodium contents. Treatment of animals with dantrolene sodium (4 mg/hr) throughout the periods of ischemia and reperfusion was found to preserve the ultrastructural appearance of quadriceps, soleus and anterior tibialis muscles. No effect of dantrolene sodium on indicators of free radical activity or muscle cation content was seen.

Advances in isotope methods for the analysis of trace elements in man

ADVANCES IN STABLE ISOTOPE METHODOLOGY History Using Stable Isotopes to Study Trace Element Metabolism Stable Isotope Dosage, Preparation, and Administration Conducting Stable Isotope Tracer Studies ADVANCES IN RADIOISOTOPE METHODOLOGY Radioisotopes Whole-Body Counting Techniques Body Imaging Techniques Indirect Measurements of Absorption or Metabolism Concluding Remarks TRACER TO TRACEE RATIO FOR COMPARTMENTAL MODELING OF STABLE ISOTOPE DATA Introduction Single Pool Tracer Kinetics and Measurement Tracer to Tracee Ratio from Mass Spectrometry Measurements Multi Pool Tracer Kinetics and Measurement The Multiple Tracer Case A Test of the Endogenous Constant Steady State Assumption Software Tool: TTRM Conclusions METHODS FOR ANALYSIS OF TRACE ELEMENT ABSORPTION Introduction Iron Copper Zinc Selenium KINETIC STUDIES OF WHOLE BODY TRACE ELEMENT METABOLISM Introduction General Considerations in Study Design Compartmental Modeling Specific Examples of Isotope Turnover Studies Concluding Remarks STABLE ISOTOPE METHODS FOR THE INVESTIGATION OF IRON METABOLISM IN MAN Introduction Erythrocyte Incorporation and Iron Absorption Zinc Zinc and Copper Selenium Chromium Conclusions USE OF ISOTOPES IN THE ASSESSMENT OF ZINC STATUS Introduction Isotopic Techniques Conclusions COPPER STATUS AND METABOLISM STUDIED WITH ISOTOPIC TRACERS Introduction Background Copper Status Isotopic Tracers Conclusions USE OF STABLE ISOTOPES OF SELENIUM TO INVESTIGATE SELENIUM STATUS Introduction Dietary Selenium and Its Metabolism The Role of Selenium in the Body Assessment of Selenium Status and Use of Stable Isotopes Conclusions USE OF ISOTOPES FOR STUDIES WITH MANGANESE, CHROMIUM AND MOLYBDENUM Manganese Chromium Molybdenum Summary TRACE ELEMENT STUDIES IN INFANTS AND PREGNANT OR LACTATING WOMEN Introduction Iron Zinc Zinc and Copper Selenium Chromium Conclusions STABLE ISOTOPE STUDIES IN THE ELDERLY Introduction Practicalities of Working with Elderly Subjects Ethical Considerations Examples of Stable Isotope Studies in the Elderly Selenium Status of the Elderly Conclusions APPLICATIONS OF TRACE ELEMENT STUDIES IN DEVELOPING COUNTRIES: PRACTICAL AND TECHNICAL ASPECTS Introduction Applications of Isotope Studies in Developing Countries Practical Aspects of Implementing Isotope Studies in Developing Countries Technical Aspects of Implementing Isotope Studies in Developing Countries Conclusions

The relationship between zinc intake and serum/plasma zinc concentration in pregnant and lactating women: A systematic review with dose-response meta-analyses

Recommendations for zinc intake during pregnancy and lactation vary widely across Europe. Using data on zinc intake and biomarkers of zinc status reported in randomized controlled trials (RCTs) and observational studies can provide estimates of dose-response relationships that may be used for underpinning zinc reference values. This systematic review included all RCTs, prospective cohort studies, nested case-control studies and cross-sectional studies in healthy pregnant and lactating populations published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient (βˆ) was calculated for each individual study and calculated the overall pooled βˆ and SE (βˆ) using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status found that a doubling of zinc intake was associated with an increase in serum/plasma zinc status by 3% in pregnant women and by 1% in lactating women. These modest associations are likely to reflect the low-moderate zinc bioavailability dietary patterns and the widespread use of other micronutrients in the populations included in this review, physiologic adjustments of zinc homeostasis, insensitivity of serum/plasma zinc as a biomarker of zinc status, and wide heterogeneity between study results which reflect real uncertainty in the current evidence base. Although this review provides useful information for dietary zinc requirements in populations vulnerable to zinc deficiency, it also highlights a need for further studies in pregnant and lactating women with different dietary patterns in order to provide useful complementary evidence that can be utilized when setting zinc recommendations as a basis for nutrition policies in Europe.