minerals and bone health

The osteon is the basic unit of compact bone.

BoneHealth_osteon
Figure 1, an osteon, adapted from lecturio.com

 

Mineral wheels, aka Mulder charts

A Mulder’s chart, also known as a “mineral wheel” are often used in agriculture circles to describe mineral interactions.  Variations of this wheel are all over the Internet with no one (including us) citing the original origin.   Because these representations are “all over the place” they make good places to start a discussion.

 

BoneHealthMineralInteraction
Figure 1 A Mulder chart/mineral wheel showing mineral interactions. Strontium and silicon, while important for bone health are not in most representations on the Internet.

Calcium and phosphate are both important in bone health.  Cola, but not other carbonated beverage consumption, was found to be associated with lower bone mineral density in women, but not men (Tucker 2006).   While this site is mostly about copper, other minerals may deserve mention.

Bone is hydroxylapatite

a fancy name for Ca10(PO4)6(OH)2

10Ca(OH)2 + 6H2PO4 +2H2O → Ca10(PO4)6(OH)2 + 14H+

In examining this equation it becomes very clear that making bone, hydroxylapatite, from calcium and phosphate H2PO4 ) can become a complicated matter of where to put the 14H+. This is an acid balance issue.

Calcium, signaling and precipitation with phosphate

  • The cells of bone tissue control over 99% of the human body’s calcium content, though not calcium sensors themselves.
  • The principal calcium sensors that regulate bone calcium flux are located in the parathyroid glands.
  • Bone function is also modified by vitamin D and by calcium transport in the kidney and intestine.
  • This massive amount of transport is carried out by specialized transporters, not only for calcium, but also for other minerals needed to maintain charge balance. (Blair 2007)

 

BoneHealthOsteoblast
Figure 2, adapted from Blair (2007) figure 1. Osteoblasts, on the surface of the bone,  are connected into sheets of cells  by gap junctions containing connexin-43.  .

Pyrophosphate is derived from ATP. Everything is connected by structures called gap junctions. The osteoblasts secrete an organic matrix comprised mainly of type I collagen and other proteins (Blair 2007).

  • type I collagen,
  • small calcium binding protein osteocalcin, which facilitate mineral deposition
  • alkaline phosphatase activity which degrades pyrophosphate
  • pyrophosphate membrane transporters such as  ANKH,

 

Osteoclast degrade bone

BoneHealthOsteoclast
Figure 3, adapted from Blair (2007) and other images on the Internet. Cathepsin K and matrix metalloproteas (mmp) are proteases that degrade the collagen component of bone.

 

Copper!

We’ve covered that we have collagen in our bones.  Lysyl oxidase are a family of copper cofactor enzymes that cross-link collagen.  Copper deficiency is thought to impact bone health via lsyl oxidase (Medeiros 2016).  In a rodent model mechanical unloading was found to increase reactive oxygen species as well as increase the expression of Cu/Zn SOD1.  SOD1 deficient mice experienced greater bone loss.  Did you know that collagen in our corneas and that copper is necessary for eye health? Some think that cuprous forms of copper may be the best way of getting that copper. .

Manganese

  • Many websites give the content of manganese as 10-20mg.  Wikipedia gives a number of 12 mg.  for a normal adult human with most being in the bone followed by the liver, and the kidney. It was not clear if bone is just a storage organ with the liver and kidney being sites of accelerated metabolism.
  • Manganese induced ricketts is associated with phosphate depletion.  (Svensson 1987)
  • Calcium and parathyroid hormone increased in the sera o f manganese deficient chicks.  (Zhaojun 2013)  PTH stimulates bone resorption.

Landete-Castillejos (2012) formed a hypothesis on the role of manganese in bone from field observations.

  • Antler bone, one of the toughest of all bones was chosen as a model
  • A cold winter in Spain led to decreased Mn content of plants and ultimately a decreased Mn concentration in Antlers.
  • These antlers had decreased mechanical strength.
  • This observation led to the hypothesis called “essential mineral for calcium fixation” (EMCaF)
  • A diet depleted from Mn but not Ca produced femurs with levels lower in Mn and Ca in rats that were growing at a normal rate with no other effects of the diet. (Landete-Castillejos 2012)
  • An image search on “manganese and phosphate” was used to find a compound called purpurite.
  • On the other hand, the UniProt database contains numerous human Mn Proteins.  of which the manganese superoxide dismutase 2 (SOD2) is one.
  • UnitProt also has even more plant Mn Proteins.  The sweet potato purple acid phosphatase probably has the most interesting sounding name.  This protein uses a aspartic acidic, an asparagine, and two histidines to coordinate manganese.
BoneHealth_manganese
Figure 4.  Manganese complexes A. with phosphate, aka purpurite B. with SOD2, UnitProt.org  C. the sequence of SOD2 with the Mn binding sites noted with orange boxes. H, histdine, D, aspartic acid.

What does manganese do in bone?  It could form complexes with the phosphate or it could form complexes histidines and other amino acids in collagen.  CuCl2  is plant copper.  MnPO4  is plant manganese.  In the opinion of Mitosynergy, minerals for humans should come as organic complexes,.

Magnesium, technology imitating nature

Magnesium and magnesium oxide have become favorite doping agents for synthetic hydroxyl apatite used for bone rebuilding and other tissue engineer applications. Magnesium is important for cell-extracellular matrix interactions and bone apatite structure and density (Hickey 2015).

Strontium

These are some tidbits when we first started looking at bone minerals a few years ago.

  • Strontium ranelate increases the proliferation of pre-oseoblasts (make hydroxyapetite) as well as the production of collagen. (Fonseca 2008)
  • In addition to the osteoporosis approved drug strontium ranelate, Sr fructose, 1,6-diphosphate, and strontium citrate have also proven effective in treating osteoporosis. (Tan 2014)

A Marx (2020) review seeks to add clarity to the confusion of what this element in the same periodic group as calcium is doing in bone.

  • The Ca-sensing receptor (CaSR)  that regulates parathroid hormone senses strontium as well.
  • CaSR is in osteoblasts
  • CaSr is in osteoclasts
  • In mineralization, Sr substitutes for Ca in hydroxy apatite.
  • Sr interacts with collagen
  • Sr can coordinate with 8 oxygens

We are showing the sequence of one of the repeats of collagen 1.

Note that collagen may also be glycosylated with polysaccharides, hexagons in figure 5B.

BoneHealth_strontium
Figure 5 Strontium in bone health  A Marx proposed oxides of strontium bind to collagen fibres.  B.  Collagen fibers exist as triple helices with repeating sequences.  One such repeat is shown.  Glutamic acids are noted with orange boxes  C.  the SER sequence shown in panel B might bind phosphate and calcium or strontium.

Marx (2020) claim that hydroxyapatite precipitates on collagen fibers (Fig 5A).  How?  Figure 5B shows one repeat of one of three giant monomers in a collagen fiber.  Note the glutamic acids (E).  We also need to remember that collagen fibers are glycosylated.  Figure 5C shows the structure of a Serine-glutamic acid-arginine peptide.  Yeah, it kind of makes sense that hydroxy apatite might precipitate onto collagen.  Strontium is in the same periodic group as calcium.  How its larger atomic radius makes a difference in bone health is beyond the scope of this post.

Silicon

The  Jugdaohsingh (2007) review was interesting but hard to visualize.  Here are dome key points:

  1. Si(OH)4 interacts readily with alkyl diols of sugars to form five and six-coordinate Si complexes suggesting that interactions with bio-molecules is possible. Are these similar to borate interactions with vicinal cis-diols?
  2. Plants produce biogenic (phytolithic) silica which is often associated with the polysaccharide/carbohydrate components of the cell wall
  3. Monocot grains generally accumulate 10-20x as much silica as dicot legumes.
  1. Orthosilicic acid is thought to be the breakdown of phytosillicates that actually gets absorbed.
  2. In the rat highest levels or orthosilicates found in bone and other connective tissues such as, skin, nail, hair, trachea, tendons and aorta and very much less (10-20 fold less) in soft tissues
  3. Orthosilicic acid have also reported increases in type I collagen synthesis and cellular differentiation
  4. High levels of Si were found to be strongly bound to connective tissues and its components, namely glycoaminoglycans, polysaccharides and mucopolysaccharides.
  5. Silicon has also been found at the mineralization front of growing bone

 

Bhattacharjee H, Mukhopadhyay R, Thiyagarajan S, Rosen BP (2008) Aquaglyceroporins: ancient channels for metalloids J Biol. 2008; 7(9): 33.

BoneHealth_silica
Figure 6.  Silicate forms bonds with molecules with hydroxyl groups A. Periodic table of elements. Inset contains image of silicate acid B. Silica complexing with vicinal hydroxyl groups of two mannose molecules.

Mannose is a six carbon sugar present in polysaccharides of the extracellular martix.   Lysyl oxidase increases bone strength by cross-linking lysine residues in collagen.  Any secreted protein or surface protein that is glycosylated with mannose or other sugars may be cross-linked by silica.

Borate/Boron

Nielsen (2016) reviewed some of the physiological functions of borate

  1.  Boron binds nicotinamide adenine dinucleotide (NAD+) with high affinity.  Whether boron acts on intracelular and/or extracellular NAD+was not that clear in this review.
  2. One role of extracellular NAD+ is binding to the plasma membrane receptor CD38, an adenosine diphosphate ribosyl cyclase that converts NAD+ to cyclic ADP ribose.
  3. Cyclic ADP ribose is released intracellularly and binds the ryandodine receptor,which induces the release of calcium ions from the endoplasmic reticulum.
  4. Cell culture studies show that boron binds to and is a reversible inhibitor of cyclic ADP ribose
  5. Boron in concentrations that are found in blood was found to decrease Ca2+ release from ryandodine receptor-sensitive stores.
  6. It has been hypothesized that boron is bioactive through binding NAD+ and/or cyclic ADP ribose and inhibiting the release of Ca2+, which is a signal ion for many processes affected by boron, including insulin release, bone formation, immune response, and brain function.

Forrest Nielsen has done a lot of work in bone and tooth strength in rabbits with boron supplementation. There’s also the component of high energy diet. To be honest, borate binds to so many compounds with cis-vicinal hydroxyl groups, it’s kind of hard to tell which of many possible interactions are the important ones.  Another review, Park (2006) covered boron in plants and animals.  In reviewing both of these reports it is important to remember that borate binds carbohydrates

BoneHealth_boron
Figure 7 Boron in bone health A. Structure of NADH and NAD+ . A red box is drawn around one of the ribose sugars. B. Borate binding to ribose C. The borate transporter described by Park (2006)
  • Boron stabilizes NADH oxidase in plants
  • In mammalian tissue too. Highest concentrations are in bone, heart, spleen, and liver.
  • Required for a hydroxylation step in the synthesis of testosterone, and 17-β-estradiol.
  • Bor1 and NaBC1 are plant and mammalian homologs of the same transporter.
  • In a study of cultured cells, 0.1 to 1mM borate promoted proliferation. 10mM borate was cytotoxic.

Conclusion

Note that all of the minerals covered in this bone health post bind to organics.  Bone is very much an organic material in addition to the hydroxy apatite most of us learned in school.    Perhaps we need to throw that mineral wheel when it comes to mineral supplements for humans.  As of this posting, Mitosynergy only sells cuprous niacin, not the other minerals.    Thank you for reading!

References

Bhattacharjee H, Mukhopadhyay R, Thiyagarajan S, Rosen BP (2008) Aquaglyceroporins: ancient channels for metalloids J Biol. 2008; 7(9): 33.

Blair HC, Schlesinger PH, Huang CL, Zaidi M.(2007)Calcium signaling and calcium transport in bone disease. Subcell Biochem.45:539-62. Review.

Fonseca JE (2008) Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength Rheumatology (Oxford) 2008 July; 47(Suppl 4): iv17–iv19.

Kim MH, Bae YJ, Choi MK, Chung YS.(2009) Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption. Biol Trace Elem Res. 2009 Jun;128(3):239-47.

Hickey DJ, Ercan B, Sun L, Webster TJ.(2015) Adding MgO nanoparticles to hydroxyapatite-PLLA nanocomposites for improved bone tissue engineering applications. Acta Biomater. 14:175-84.

Jugdaohsingh R (2007) Silicon and bone health J Nutr Health Aging. 11(2): 99–110.

Landete-Castillejos T, Molina-Quilez I, Estevez JA, Ceacero F, Garcia AJ, Gallego L. (2012)
Alternative hypothesis for the origin of osteoporosis: the role of Mn. Front Biosci (Elite Ed). 2012 Jan 1;4:1385-90.

Marx D, Rahimnejad Yazdi A, Papini M, Towler M. (2020) A review of the latest insights into the mechanism of action of strontium in bone. Bone Rep. 2020 Apr 24;12:100273.

Medeiros DM. (2016) Copper, iron, and selenium dietary deficiencies negatively impact skeletal integrity: A review. Exp Biol Med (Maywood). 2016 Jun;241(12):1316-22

Morikawa D, Nojiri H, Saita Y, Kobayashi K, Watanabe K, Ozawa Y, Koike M, Asou Y, Takaku T, Kaneko K, Shimizu T. (2013) Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. J Bone Miner Res. 2013 Nov;28(11):2368-80

Nielsen FH (2014) Update on human health effects of boron. J Trace Elem Med Biol.28(4):383-7..

Park M, Li Q, Shcheynikov N, Muallem S, Zeng W.(2005) Borate transport and cell growth and proliferation. Not only in plants. Cell Cycle. 4(1):24-6.

Svensson O, Engfeldt B, Reinholt FP, Hjerpe A.(1987) Manganese rickets. A biochemical and stereologic study with special reference to the effect of phosphate. Clin Orthop Relat Res. 1987 May;(218):302-11.

Tan S, Zhang B, Zhu X, Ao P, Guo H, Yi W, Zhou GQ.(2014)Deregulation of bone forming cells in bone diseases and anabolic effects of strontium-containing agents and biomaterials.Biomed Res Int. 2014:814057

Tucker KL, Morita K, Qiao N, Hannan MT, Cupples LA, Kiel DP.(206)Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study. Am J Clin Nutr. 2006 Oct;84(4):936-42. doi: 10.1093/ajcn/84.4.936.

Zhaojun W, Lin W, Zhenyong W, Jian W, Ran L.(2013) Effects of manganese deficiency on serum hormones and biochemical markers of bone metabolism in chicks. J Bone Miner Metab. 31(3):285-92

Published by BL

I like to write educational websites

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