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2021, Number 2

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Acta Ortop Mex 2021; 35 (2)

An overview on the correlation between blood zinc, zinc intake, zinc supplementation and bone mineral density in humans

Rondanelli, M1,2; Peroni, G3; Gasparri, C3; Infantino, V2; Naso, M3; Riva, A4; Petrangolini, G4; Perna, S5; Tartara, A3; Faliva, MA3

Language: English
References: 40
Page: 142-152
PDF size: 215.60 Kb.


ABSTRACT

Introduction: In case of zinc (Zn) deficiency, this mineral becomes a nutrient limiting muscle and bone synthesis. The study in humans on zinc and bone health are few and no reviews have been published on this topic. So, the aim of this narrative review was to consider the state of the art on the correlation between blood zinc, daily zinc intake, zinc supplementation and bone mineral density. Material and methods: A narrative review was performed. Results: This review included 16 eligible studies: eight studies concern Zn blood; three studies concern Zn intake and five studies concern Zn supplementation. Conclusion: Blood zinc levels seem to be lower in subjects with pathology related to bone metabolism. Regarding daily zinc intake, a high proportion of the population, more than 20%, seems to be at risk of having inadequate zinc intake. The literature suggests that an insufficient zinc intake (less than 3 mg/day) could be a risk factor for fractures and for development of osteopenia and osteoporosis. Zinc supplementation (40-50 g/day) could have beneficial effects on bone health in terms of maintaining bone mineral density and faster healing in the event of fractures, with even better results in situations of reduced intake zinc through food.



INTRODUCTION

Zinc is an essential component for our body. Over 85 percent of body zinc total is found in skeletal muscles and bones,1 while zinc contained in plasma represents only 0.1 percent of the total and its concentration, strictly regulated, varies from about 10 to 15 μmol/l. Zinc plasma concentrations are maintained without significant changes even when zinc intake has decreased or increased, unless these changes in intake are severe and prolonged.2

It is widely distributed in food, but the best food sources are meat, eggs, fish, cheeses and cereals.3

The RDA for adult men is 8 mg per day while for adult women it is 11 mg per day.4

Since zinc in foods is not present as a free ion, bioavailability depends on the extent of digestion. With digestion zinc has the opportunity to bind to exogenous and endogenous components in the intestinal lumen (peptides, amino acids, nucleic acids and other organic acids and inorganic anions) to be absorbed through a transcellular process in fasting, which is the site with the higher transport speed.5,6,7

The homeostatic regulation of zinc metabolism is mainly achieved through a balance between absorption and secretion of endogenous reserves that involve adaptive mechanisms programmed by the intake of zinc in the diet.1

These losses can vary from less than 1 mg/day with a low zinc diet to more than 5 mg/day with a zinc rich diet, to underline the important regulatory role that the intestinal tract plays in zinc homeostasis.1

Zinc concentrations decreased rapidly in humans fed a diet with a very low zinc content and containing phytates.8

Zinc is a fundamental constituent of various enzymes that play a role in maintaining the structural integrity of proteins and in regulating gene expression; there are almost 100 specific enzymes that depend on zinc for catalytic activity.4

Its biological functions can be divided into three categories: catalytic, structural and regulatory.9

Among the many functions performed by zinc (for example the maturation of the cells of the immune system and the prevention of lipid peroxidation by reducing the formation of free radicals) also includes the formation of bones and muscles where, in case of deficiency, it becomes a nutrient limiting this synthesis. It also has an important role in stimulating the synthesis of alkaline phosphatase in osteoblasts.10



ZINC AND BONE DEVELOPMENT: IN VITRO AND IN ANIMAL MODEL STUDIES

In vitro it has been shown that the proliferation of osteoblastic cells has been stimulated after zinc culture with an inhibitory effect on the formation of osteoclastic cells.11,12,13,14,15,16 Furthermore, always in vitro, zinc modulates the anabolic effect of 1,25-dihydroxyvitamin D3 or of estrogens on bone metabolism in vitro.17 The same anabolic effect is confirmed in animal studies.18,19 as well as the role of osteoblastic stimulation and osteoclastic inhibition is confirmed.20,21,22 Also in animals it has been shown that zinc deficiency seems to interfere with bone metabolism with consequent reduction of bone formation23 and causes criticalities in bone consolidation in the spine;24 in another study it is highlighted how zinc deficiency can lead to a reduction in serum calcium concentration and to an increase in parathyroid hormone with subsequent bone fragility.25

Despite this background, the study in humans on zinc and bone health are few and no reviews have been published on this topic. So, the aim of this narrative review was to consider the state of the art on the correlation between blood zinc, daily zinc intake, zinc supplementation and bone mineral density.



MATERIAL AND METHODS

The present narrative review was performed following the steps by Egger et al.26 as follows:

  • 1. Configuration of a working group: three operators skilled in clinical nutrition (one acting as a methodological operator and two participating as clinical operators).
  • 2. Formulation of the revision question on the basis of considerations made in the abstract: "the state of the art on the correlation between human blood zinc concentrations, daily zinc intake with food, zinc supplementation and bone mineral density".
  • 3. Identification of relevant studies: a research strategy was planned on PubMed (Public MedIine run by the National Center of Biotechnology Information [NCBI] of the National Library of Medicine of Bethesda [USA]) as follows: (a) Definition of the keywords (zinc, bone health, humans, intake, supplementation, bone mineral density), allowing the definition of the interest field of the documents to be searched, grouped in quotation marks ("…") and used separately or in combination; (b) use of: the Boolean (a data type with only two possible values: true or false) AND operator, that allows the establishments of logical relations among concepts; (c) Research modalities: advanced search; (d) Limits: time limits: papers published in the last 30 years; humans; adults; languages: English; (e) Manual search performed by the senior researchers experienced in clinical nutrition through the revision of articles on the state of the art on the correlation between human blood zinc concentrations, daily zinc intake with food, zinc supplementation and bone mineral density.
  • 4. Published in journals qualified in the Index Medicus.
  • 5. Analysis and presentation of the outcomes: we create paragraphs about the state of the art on the correlation between human blood zinc concentrations, daily zinc intake with food, zinc supplementation and bone mineral density, and the data extrapolated from the "revised studies" were collocated in tables; in particular, for each study we specified the author and year of publication and study characteristics.
  • 6. The analysis was carried out in the form of a narrative review of the reports. At the beginning of each section, the keywords considered and the type of studies chosen are reported. We evaluated, as is suitable for the narrative review, studies of any design which considered the the state of the art on the correlation between human blood zinc concentrations, daily zinc intake with food, zinc supplementation and bone mineral density. Figure 1 shows the flow chart of literature research.



RESULTS



BLOOD ZINC CONCENTRATIONS IN RELATION TO BONE METABOLISM

This research was conducted based on the keywords: "zinc" AND "zinc blood concentrations" and "bone" and "humans". For the present review we have analyzed a total of eight studies: five cross-sectional studies, two case-control studies and one clinical trial.

The results of these eight studies have been shown in Table 1.

Data from three studies, from 1983 to 2007, agree on a reduction in zinc values in osteoporotic women compared to healthy controls. In 1983 Atik took into consideration 22 women aged between 48 and 86 and found significantly lower blood zinc values in women with osteoporosis compared to healthy controls.27

In a study from the early 2000s, the same two groups of postmenopausal women (70 with osteoporosis and 30 healthy) were compared to the same conclusion as the previous study.28

In 2007 Mutlu et al. added osteopenic subjects to the comparison, for a total of 120 menopausal women divided into three groups (osteoporotic, osteopenic, healthy), concluding that the blood zinc levels in women with osteoporosis were significantly lower than osteopenic and healthy women, and which in turn women with osteopenia had significantly decreased blood zinc levels compared to healthy controls.29 In the 2013 study by Okyay, zinc deficiency is directly defined as an independent risk factor for developing osteoporosis and in the researh it is specified how this deficiency is related to lumbar osteoporosis both in the 45-59 years and 60-80 age groups years.30

At an intermediate level there are two other studies, from 2009 and 2011. Liu et al in 2009 define the existence of a difference in blood zinc levels between osteoporotic, osteopenic and healthy women, but that however this difference is not statistically significant.31 Two years later, in 2011 Arikan reaches the same conclusion by comparing the same three groups.32

Unlike these studies, in 1995 Relea et al, found statistically significant differences between osteoporotic and healthy women, not in the blood zinc levels (which are not different in this study), but in the urinary zinc excretion which is increased in a way significant in women with osteoporosis compared to healthy controls.33

The study by Mahdavi-Roshan published in 2015 is totally opposite, where there is no difference in plasma zinc levels in the comparison between women with osteopenia and healthy women.34



ZINC INTAKE IN RELATION TO BONE METABOLISM

This research was conducted based on the keywords: "zinc" and "zinc intake" and "bone" and "humans".

For the present review we have analyzed a total of three studies: two cohort studies and one cross-sectional study.

The results of these three studies have been shown in Table 2.

The daily zinc intake with food in relation to bone metabolism is analyzed in three studies, two of which substantially agree in the results.

In 1998, Elmstahl and colleagues study a large male population, consisting of 6,576 Swedish men aged between 46 and 68 years, concluding that low zinc intakes are a risk factor for fractures and that about 20% of the population studied took on inadequate quantities.35 The same results emerged from study by Hyun's 2004 conducted on 396 men, where zinc intake levels are significantly reduced in subjects with osteoporosis.36

Different results emerge from the 2015 Mahdavi-Roshan study on 51 menopausal women, where no difference in zinc intake was observed between women with osteoporosis, osteopenia and healthy; however, the study shows a general zinc intake lower than the values recommended by the RDA.34



ZINC SUPPLEMENTATION IN RELATION TO BONE METABOLISM

This research was conducted based on the keywords: "zinc" and "zinc supplementation" and "bone" and "humans".

For the present review we have analyzed a total of five studies: three double-blind placebo controlled trials, one clinical trial and one randomized controlled trial.

The results of these five studies have been shown in Table 3.

As regards zinc supplementation, both alone and in associations with other nutrients, all the studies identified are substantially in agreement in defining beneficial effects for the bone (Table 3).

Already in 1974, in a study carried out on adolescents for 18 months, comparing an integration with 40 mg of zinc against placebo, there was an increase in bone age and bone development in the integrated group, with better results especially after 12 months of integration.37

The effect of a zinc-only supplement on 60 men and women with fractures is also evaluated in the study by Sadighi in 2008; the subjects were divided into two groups destined to receive 220 g of zinc sulphate (corresponding to 50 g of zinc) or placebo and the final results show that in the group of subjects treated with zinc there was a faster healing of the fracture and significant change in bone callus formation 60 days after fracture.10

In other three papers the effects of zinc in association with other nutrients are studied.

The study by Strause in 1994 involved healthy postmenopausal women divided into four groups (calcium supplement + micronutrient supplement, calcium supplement + micronutrient placebo, calcium placebo + micronutrient supplement, calcium placebo + micronutrient placebo), where the group that received both calcium and micronutrient supplementation, including zinc, maintained lumbar bone mineral density with a significant difference compared to the group that received only placebo; the remaining two groups positioned themselves at an intermediate level, without showing significant differences with the treated group or with the placebo group.38

Subsequently, in 2011, the study by Nielsen and colleagues compares calcium supplementation versus calcium supplementation associated with zinc and copper in a group of menopausal women; the results confirm that zinc could bring beneficial effects on bone health only if the intake of zinc with diet is reduced (< 8 mg per day), while there were no significant beneficial effects with adequate zinc intake.39

Always the same author, a few years earlier, wanted to check whether zinc supplementation could lead to changes in copper metabolism such as to lead to changes in bone turnover. The results did not lead to defining significant changes in copper metabolism even with high zinc supplements (53 mg per day), while this supplement led to an excessive excretion of magnesium. Low doses of zinc (3 mg per day) have instead caused unwanted changes in circulating osteocalcin and calcitonin.40



CONCLUSION

We can define that blood zinc levels seem to be lower in subjects with pathology related to bone metabolism. The literature suggests that an insufficient daily intake of zinc through nutrition (less than 3 mg/day) could be a risk factor for fractures and for the development of osteopenia and osteoporosis. A high proportion of the population, more than 20%, seems to be at risk of having inadequate dietary habits with respect to zinc. The supplementation of zinc in an amount equal to 40-50 g, on the other hand, could have beneficial effects on bone health in terms of maintaining bone mineral density and faster healing in the event of fractures, with even better results in the situation of reduced zinc intake through food.


REFERENCES

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AFFILIATIONS

1 IRCCS Mondino Foundation.

2 Department of Public Health, Experimental and Forensic Medicine, University of Pavia.

3 Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona "Istituto Santa Margherita", University of Pavia.

4 Research and Development Department, Indena SpA.

5 Department of Biology, University of Bahrain, College of Science, Sakhir Campus.



Conflict of interest: None.



CORRESPONDENCE

Gabriella Peroni, MD. E-mail: gabriella.peroni01@universitadipavia.it




Recibido: 21-01-2021. Aceptado: 25-07-2021.

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