Osteoporosis

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Supplements on the ‘supplements too be avoided’ list on the Treatment page would have to be avoided. Coffee, sodas and tea should be limited. Supplements that supply cysteine would have to be avoided. Supplementation with cysteine, cystine, n-acetyl-cysteine, l-methionine and/or s-adenosyl-l-methione would all have to be avoided. Lipoic acid must not be supplemented.

Osteoporosis: focus on the transsulfuration pathway  

Thomas Berry1, Ahmed A. Moustafa1,2,3

1School of Psychology & 2Marcs Institute for Brain and Behaviour, Western Sydney University, Sydney, New South Wales, Australia.

3 Department of Human Anatomy and Physiology, the Faculty of Health Sciences, University of Johannesburg, South Africa  

Abstract


Treatment of osteoporosis is now far from optimal. In osteoporosis risks of fractures increase with increased homocysteine levels. The transsulfuration pathway metabolizes homocysteine to L-cysteine. Increased homocysteine levels indicate that that the transsulfuration pathway is dysregulated. With the transsulfuration pathway dysregulated there will be decreased levels of L-cysteine and decreased levels of taurine, which is synthesized from L-cysteine. Taurine levels are decreased in patients with osteoporosis. Taurine regulates calcium homeostasis. Taurine, also, when conjugated with bile acids assists with absorption of fats and fat-soluble vitamins such as vitamin D and vitamin K. With taurine conjugated bile acids decreased there will be reduced absorption of vitamin D, reduced absorption of calcium, which requires vitamin D for absorption, and reduced absorption of vitamin K, which is needed for bone growth.  Dysregulation of the transsulfuration pathway via an effect on calcium homeostasis and calcium absorption, vitamin D absorption and vitamin K absorption could negatively affect bone mineral density leading to osteoporosis and fractures. A combination of taurine, calcium, vitamin D and vitamin K could make a large difference in terms of increasing bone mineral density, reducing number of years lost to disability and reducing deaths due to fractures in patients with osteoporosis.      

Introduction

               Worldwide in 2000 there were an estimated 9.0 million osteoporotic fractures of which 1.6 million were at the hip, 1.7 million at the forearm and 1.4 million were vertebral fractures. (Johnell and Kanis, 2006). There were an estimated 3,125,000 Disability Adjusted Life Years (DALYs) in 1990 due to low bone mineral density (BMD) with DALYs rising to 5,216, 000 in 2010 (Sànchez-Riera et al. 2014).  Extrapolating from Swedish data In 1990 there were an estimated 740,000 deaths  worldwide associated with hip fractures (Johnell and Kanis, 2004). In 2017, the annual cost of new fragility fractures in the five largest nations in the European Union plus Sweden was estimated to be €37.5 billion in 2017 with annual costs expected to rise by 27% by 2030 (Borgström et al., 2020). Opioids are a mainstay in the treatment of moderate and severe pain associated with osteoporosis (Vellucci et al., 2016; Vellucci et al., 2018). However, a meta-analysis indicates that opioid use increases the risk of hip fractures (Ping et al., 2017). With use of opioids there is an increased risk of falls, fall injuries, and fractures among older adults (Yoshikawa et al., 2020).  Treatments that decrease incidences of fractures negating a need for opioids would be optimal. 

               Incidences of fractures associated with osteoporosis could be reduced by treatment with taurine, vitamin D, vitamin K and calcium. High levels of homocysteine could lead to low levels of taurine, dysregulation of intracellular calcium homeostasis, low levels of vitamin D, decreased calcium absorption  and low levels of vitamin K with attendant decreases is bone mineral density (BMD) and increases in bone fractures as seen is osteoporosis.

Homocysteine and bone abnormalities

                In older men and women increased plasma homocysteine levels are a strong risk factor for osteoporotic fractures with a 1.4 increase in risk for each 1 SD increase in the natural-log-transformed plasma homocysteine level (van Meurs et al., 2004).  High plasma homocysteine levels increase the probability of a hip fracture (Gjesdal et al., 2007;  Leboff et al., 2009). Men in the highest quartile of plasma homocysteine compared to men in the lowest quartile had almost 4 times the risk of hip fracture while women in the highest quartile of plasma homocysteine had an increased relative risk of 1.9 compared to women in the lowest quartile (McLean et al., 2004). Fractures are significantly associated with high plasma levels of homocysteine in healthy elderly individuals  (Dhonukshe-Rutten et al., 2005). In terms of plasma homocysteine a meta-analysis, where there were 14,863 participants, indicated that in the highest quartile there is a 1.67 relative risk for fractures compared to individuals in the lowest quartile (Yang et al.,  2012). A meta-analysis indicates that supplementation with folic and vitamin B12, which decrease homocysteine levels by increasing the re-methylation of homocysteine to L-methionine.  does not lower the risk of fractures (Garcia Lopez et al., 2018). Decreasing homocysteine by increasing re-methylation would not re-regulate the transsulfuration pathway. Inability of folic acid and vitamin B12 to reduce relative risks for fractures points to high homocysteine levels in osteoporosis being a marker for dysregulation of the transsulfuration pathway in osteoporosis.

               Among middle-aged and elderly women plasma levels of homocysteine were inversely associated with bone mineral density (Gjesdal et al., 2006). Lumbar spine, femur neck and total hip bone mineral density (BMD) are inversely correlated with serum homocysteine levels (Bahtiri et al., 2015).Plasma homocysteine is a predictor of BMD where high plasma homocysteine levels are associated with low BMD (Krivosíková et al., 2009).

Taurine, calcium, vitamin D, and vitamin K in osteoporosis  

               Taurine is synthesized from L-cysteine (Jacobsen and Smith, 1968; Beetsch and Olson, 1998). L-cysteine is synthesized from homocysteine via the transsulfuration pathway (Sbodio et al., 2019).   High homocysteine levels point to the dysregulation of the transsulfuration pathway (Vitvitsky et al, 2006).  With the transsulfuration pathway dysregulated sufficient L-cysteine and sufficient taurine will not be synthesized. Taurine can normalize hyperhomocysteinemia in rabbits fed an atherogenic die (Zulli et al., 2009). Taurine supplementation in humans decreases plasma homocysteine levels (Ahn, 2009).  Taurine supplementation in humans increases activities of cystathionine beta-synthase and cystathionine gamma-lyase (Sun et al., 2016), the two enzymes in the transsulfuration pathway, which could explain the homocysteine lowering effects of taurine.

               Dysregulated calcium homeostasis could lead to bone abnormalities seen in osteoporosis. Taurine regulates intracellular calcium homeostasis (Foos et al., 2002; Chen et al., 2001). El Idrissi and Trenkner, 2003; El Idrissi and Trenkner, 1999. El Idrissi, 2006). With taurine deficiencies intracellular calcium homeostasis could be dysregulated though there are near normal calcium serum levels or normal calcium serum levels. With taurine deficiencies there could be a dysregulation of intracellular calcium in osteoblasts and osteoclasts leading to decreased bone growth and increased bone resorption.  

               Taurine conjugated to cholic acid and chenodeoxycholic form the bile acids taurocholic acid and taurochenodeoxycholic acid respectively (Sjovall, 1959; Vessey, 1978)  Bile acids are needed for fat absorption (Hofmann et al., 1964; Austad et al., 1987) and assist with absorption of fat-soluble vitamins (Di_Ciaula et al., 2017; Heubi et al., 2007). Even in the absence of clinical steatorrhea there can be vitamin D deficiencies as fat-soluble vitamins are highly sensitive to disturbances is lipid absorption (Lo et al., 1985). Genetic defects in bile acid synthesis can cause fat-soluble vitamin deficiencies (Setchell et al., 2013). Taurine supplementation increases absorption of vitamin D (Zamboni et al., 1993). Vitamin D regulates the taurine transporter (Chesney and Han, 2013).

               In women receiving treatment for osteoporosis there is frequently vitamin D insufficiency with serum 25(OH)D less than 20 ng/ml in 18%, less than 25 ng/ml in 36%; and less than 30 ng/ml in 52% (Holick et al.,  2004). The odds ratio for osteoporosis was 4.17 for women who had an insufficiency of vitamin D (Mezquita et al., 2001). Postmenopausal women with established vertebral osteoporosis had a prevalence of hypovitaminosis D, defined as 25OHD < or = 30 nmol/l, of 39% (Sahota et al.., 2004).   In children with osteopenia or osteoporosis 80% had vitamin D insufficiency with serum 25-hydroxyvitamin D <30 ng/mL. (Bowden et al., 2008). 

               Bile salts are required for vitamin K absorption (Shearer et al., 2012; van Meurs et al., 2009)  Vitamin K is involved in bone formation.  Decreased serum levels of vitamin K in post-menopausal women are associated with bone loss (Kanai et al., 1997). The risk of hip fractures in women is increased by low intakes of vitamin K (Feskanich et al., 1999). Vitamin K supplementation can increase bone density and reduce fracture rates (Weber, 2001).

               Vitamin K is required for carboxylation of gamma-carboxyglutamic (GLA) domains (Zittermann et al., 2001).  Carboxylation GLA domains helps proteins with GLA domains bind calcium (Vermeer, 1990).  Osteocalcin, which has GLA domains,  is synthesized only in osteoblasts  where carboxylated osteocalcin binds calcium and assists with bone growth (Neve et al., 2013; Lian et al., 1988).  Supplemental taurine could assist with the absorption of vitamin K promoting bone growth.

Increasing bone formation and decreasing bone resorption with taurine, vitamin D, vitamin K and calcium  

                Taurine is found at high levels in bone (Lubec et al., 1997). Taurine both stimulates bone formation and inhibits bone resorption (Gupta and Kim, 2003). The taurine transporter is found in osteoblasts, which are bone forming cells,  with taurine playing a role in bone homeostasis (Yuan et al.,2006). Taurine stimulates osteoblast formation (Zhou et al., 2014). Increases in osteoblasts due to taurine could be due to the stimulation of the ERK pathway (Zhou et al., 2014). Taurine inhibits formation of osteoclasts (Yuan et. al., 2010; Koide et al. 1999), which break down bone.   

               In humans healthy controls have higher serum taurine levels than osteoporosis patients (Pontes et al., 2019). Low taurine levels in urine are a marker of post-menopause  and osteoporosis with taurine levels in urine decreasing 1.6 fold in post-menopausal women compared to pre-menopausal women  (Yu et al., 2019). One of the ways bisphosphonates could work in osteoporosis could be by increasing taurine levels. In ovariectomized mice alendronate sodium, a bisphosphonate, increases taurine levels from 467.6±116.0 uM to 669.2±127.6 uM (Chen et al. 2014). In retinal capillary endothelial cells  [(3)H]taurine uptake was increased significantly by pretreatment with alendronate and pamidronate (Lee et al., 2013). In vitro taurine like alendronate, a bisphosphonate used to treat osteoporosis, inhibits bacteria-stimulated osteoclast formation (Kum et al., 2003).  

               Another route by which taurine could increase bone formation is by inhibiting the reverse mode of the Na+/Ca2+ exchanger (NCX). NCX exports calcium from cells while importing Na, however, in reverse mode the Na+/Ca2+ exchanger imports Ca2+ and exports Na+ (Zhang  et al., 2004). Taurine inhibits the reverse mode of NCX (Chen et al., 2001; Wu et al., 2000; Wu et al., 2010). Osteoblasts express NCX where NCX is located on the mineralizing side of osteoblasts  (Stains et al.,  2002; Stains et al., 1998; Sosnoski and Gay, 2008). Osteoblasts in forming bone export calcium via NCX into the growing bone matrix. Taurine by inhibiting the reverse mode of the NCX in osteoblasts could assist with the formation of bone. Osteoclasts also express NCX variants where NCX mediate calcium transport during bone resorption (Li et al., 2007).   Inhibition of the reverse mode of NCX by taurine could increase bone growth by osteoblasts and prevent bone resorption by osteoclasts.         

               1,25-dihydroxyvitamin D is  involved in calcium homeostasis (Veldurthy et al., 2016; Goltzman et al., 2018. Khammissa et al., 2018).  Vitamin D enhances calcium absorption (Christakos et al., 2011; Gallagher et al., 1979).  A trial of vitamin D and calcium showed a 43% decrease in hip fractures and a 32% decrease is nonvertebral fractures compared to elderly women in the placebo group (Chapuy et. al., 1992).   A meta-analysis indicates that supplementation with vitamin D and calcium can reduce total fractures by 15% and hip fractures by 30% (Weaver et al., 2015). Another meta-analysis indicates fractures are decreased more with higher dosages of vitamin D (Tang et al., 2007). Another meta-analysis, however, suggests there is little benefit towards increasing BMD with vitamin D supplementation (Reid et al., 2014).  Lack of effectiveness of vitamin D in increasing BMD could be due to vitamin D not being absorbed due to deficiencies in taurine conjugated bile acids.

               There are controversies surrounding how much vitamin D should be supplemented.  The taurine transporter is a vitamin D regulated gene (Chesney et al., 2013). Increased levels of vitamin D could increase taurine transport by the taurine transporter increasing bone growth and decreasing bone resorption.    The Institute of Medicine (USA) set the Tolerable Upper Intake Level of vitamin D at 4,000 IUs (Institute of Medicine, 2011).

               Vitamin K is a fat-soluble vitamin involved in bone via formation of gamma-carboxyglutamate residues on osteocalcin, matrix Gla-protein, and protein S.  (Vermeer et al., 1995). There are reduced vitamin K levels in post-menopausal women compared with post-menopausal women without osteoporosis (Kanai et al., 1997). In women low intakes of vitamin K are associated with decreased bone BMD (Booth et  al.,  2003). Combined supplementation with vitamin D(3) and vitamin K(2) markedly increases bone mineral density  in postmenopausal women with osteopenia and osteoporosis (Ushiroyama et al., 2002). A meta-analysis indicates than vitamin K supplementation is particularly effective in preventing fractures amongst the Japanese (Cockayne et al., 2006). Intakes of taurine are very high in Japan due to high intakes of seafood by the Japanese (Yamori et al., 2001). Vitamin K supplementation in Japan could be more effective in preventing fractures due to high intakes of taurine which assist with vitamin K absorption.

Treatment

               Calcium, vitamin D and vitamin K have all been extensively researched in the treatment of osteoporosis. We propose that a combination of calcium, vitamin D, and vitamin K combined with taurine could be a significant improvement over any one supplement. The target group for a clinical trial would be individuals with osteoporosis with raised homocysteine level and decreased taurine levels.

               There could be intracellular calcium dysregulation in osteoblasts and osteoclasts due to low levels of taurine. Vitamin D and vitamin K deficiencies that are seen in osteoporosis could be due to low levels of taurine which decrease absorption of the fat-soluble vitamin D and vitamin K. The limited effectiveness of vitamin D and vitamin K supplementation in osteoporosis could be due to vitamin D and vitamin K not being absorbed sufficiently from supplements due to row levels of taurine.

               1000-1200 mg of calcium a day would be taken in 2 divided dosages. Calcium carbonate taken with food is as well absorbed as calcium citrate (Heaney et al., 1999. The Institute of Medicine has set the Tolerable Upper Level Intake for vitamin D at 4000 IUs for adults (Institute of Medicine (US), 2011). No toxicity has been observed with vitamin K MK-7 supplementation which in better absorbed than other kinds of vitamin K (Marles et al., 2017).   The Observed Safe Level for taurine is 3000 mg. a day (Shao and Hathcock, 2008).

Discussion    

               Osteoporosis is associated with high levels of disability and death due to fractures. In patients with osteoporosis increased levels of homocysteine are associated with increased risk of fractures. Calcium, vitamin D and vitamin K have only been partly effective in the treatment of osteoporosis. Addition of taurine could increase the effectiveness of calcium, vitamin D and vitamin K in osteoporosis. The combination of taurine, calcium, vitamin D and vitamin K in the treatment of osteoporosis would be synergistic.  Taurine would be taken on empty stomach for better absorption.

               Raised homocysteine levels could be associated with decreases in taurine synthesis leading to dysregulation of intracellular calcium levels in osteoblasts and osteoclasts, decreased absorption of vitamin D, decreased absorption of calcium and decreased absorption of vitamin K whereby bone growth would be decreased and bone resorption increased leading to decreased BMD and osteoporosis. Increased levels of homocysteine with low levels of taurine tie together the threads of supplemental non-prescription approaches to osteoporosis. Some of the effects of bisphosphonates on osteoporosis could be due to bisphosphonates increasing taurine levels.

               Adding taurine to calcium, vitamin D and vitamin K would not be a major change in treatment protocols for osteoporosis, however, adding taurine could be a key change. The combination could be synergistic. Fractures due to osteoporosis are a major fear of senior citizens.   A taurine, calcium, vitamin D and vitamin K combination could increase the number of healthy lived years of senior citizens whereby senior years could be enjoyed rather than feared.  

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