**7. Natural supplements for vitamin D**

In fortified foods and supplements, vitamin D is also available in two forms, vitamins D2 (ergocalciferol) and D3 (cholecalciferol), that differ in their side-chain structure only. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol [10]. Both forms effectively raise serum 25(OH)D levels [28, 31]. It appears that at nutritional doses vitamins D2 and D3 are equivalent, but at high doses vitamin D2 is less potent.

The recent increase in vitamin D interest by the general public has fuelled a big rise in sales of over-the-counter vitamin D preparations. Additionally, products with progressively increasing content of over-the-counter vitamin D preparations are becoming increasingly prevalent. Many types of pharmaceutical preparations for vitamin D supplementation are commercially available, including oily drops, capsules and tablets [31].

Individuals at high risk for deficiency should have a vitamin D blood test first; a dosage of up to 3000–4000 IU may be required to restore blood concentrations. In the Middle East and African countries, vitamin D doses ≥2000 IU/day may be needed to reach the target 25(OH)D level ≥20 ng/ml [32].

Whilst for pregnant women and children (1000 IU daily is safe) [33], there are very few concerns regarding vitamin D complications; in the elderly and especially those who are vitamin D replete, there has been some concerns about increased falling risks (especially at high doses) [34]. A 1-year, double-blind, randomised clinical trial conducted in Switzerland of 200 community-dwelling men and women 70 years and older with a prior fall, randomised to receiving monthly 24,000 IU (low-dose), 60,000 IU of vitamin D3 and 24,000 IU of vitamin D3 plus 300 μg of calcifediol, found that the higher-dose groups increased vitamin D levels more effectively but did not improve lower extremity function (over 12 months) and indeed increased fall incidence slightly [35]. Whilst this is not a cause for alarm, the study does confirm the popular scientific idiom 'Too much of a good thing is bad thing'. Bischoff-Ferrari [36] advocates against regular high-dose bolus or monthly moderate doses of vitamin D for fracture prevention. Indeed Zhao [5] in a metaanalysis of 33 randomised trials involving 51,145 participants found no benefit of supplements containing calcium, vitamin D or both compared with places in fracture prevention among community-dwelling older adults (over 50 years); however, it is noted that the research is limited by the lack of reporting of whether participants had osteoporosis, osteopenia or low bone mass, as well as participants mainly from Europe and the United States.

In contrast, research on vitamin D replenishment in the mild to moderate vitamin D-deficient elderly population following a hip fracture showed that a single loading dose of cholecalciferol (250,000 IU vitamin D3, the REVITAHIP (Replenishment of Vitamin D in Hip Fracture) strategy) or placebo, both receiving daily vitamin D (800 IU) and calcium (500 mg), was able to improve vitamin D levels and reduce falls (**Figure 3**) and pain levels [14]. The REVITAHIP investigators adopted a similar loading dose vitamin D followed by maintenance vitamin D at 800 IU (and calcium) daily supplied to the participants, due to the very high rates of vitamin D deficiency noted in the HORIZON Recurrent Fracture study (observed in the first 385 patients [37]). The investigators found that virtually all participants in the active treatment group reached target vitamin D (>50 nmol/L) at weeks 2 and 4 compared with the placebo group (**Figure 4**).

Interestingly, Smith [38], in a group of elderly women (mean age 66 years) with hypovitaminosis D (<50 nmol/L), demonstrated that vitamin D followed

**101**

**Figure 3.**

**Figure 4.**

of 25(OH)D3 levels (**Figure 5**, [38]).

*An Evidence-Based Review of Efficacy and Safety of Dietary, Natural Supplements…*

a U-shaped curve on falls whether analysed by serum dose or serum 25(OH)D3 levels. The investigators found no decrease in the incidence of falls on low vitamin D doses (400, 800 IU), a significant decrease in falls on medium doses (1600, 2400, 3200 IU) (p = 0.020). Counterintuitively, Smith found no decrease on high doses (4000, 4800 IU) compared to placebo (p = 0.55). The rate of falls was 60% in the lowest quintile <25 ng/ml (<50 nmol/L), 21% in the low middle quintile 32–38 ng/ ml (80–95 nmol/L), 72% in the high middle quintile 38–46 ng/ml (95–115 nmol/L) and 45% in the highest quintile 46–66 ng/ml (115–165 nmol/L). A similar U-shaped pattern in the subgroup with a previous fall history was noted among the quintiles

*REVITAHIP Active Vitamin D Protocol (initial 250,000 IU followed by 800 IU Vitamin D3 and 500 mg Calcium Daily at 2, 4 and 26 weeks showed significant 25-OHD levels improvements compared with the placebo group.*

*REVITAHIP Active Vitamin D Protocol (initial 250,000 IU followed by 800 IU Vitamin D3 and 500 mg* 

Conglomerating the results from Bischoff-Ferrari, Lyles, Smith and Mak, there does not appear to be any justification in having regular high-dose vitamin D supplements at monthly intervals, due to the risk of vitamin D toxicity, hypercalcaemia and perhaps oversaturation of vitamin D receptors on skeletal muscles, leading to a propensity to falls. The author would recommend the REVITAHIP strategy of initial single loading dose bolus (250,000 IU) followed by regular 800 IU daily [14, 37], or 24,000 IU monthly [35], supplementation but would recommend to be cautious with the Smith approach of medium daily dosages, probably up to 1600 IU daily without a bolus [38], for high-risk populations, and would support that larger monthly doses

of 100,000 IU need further evaluation with respect to efficacy and safety.

*DOI: http://dx.doi.org/10.5772/intechopen.89598*

*Calcium Daily at 4 weeks shows significance in reducing falls.*

*An Evidence-Based Review of Efficacy and Safety of Dietary, Natural Supplements… DOI: http://dx.doi.org/10.5772/intechopen.89598*

**Figure 3.**

*Vitamin D Deficiency*

capsules and tablets [31].

**7. Natural supplements for vitamin D**

In fortified foods and supplements, vitamin D is also available in two forms, vitamins D2 (ergocalciferol) and D3 (cholecalciferol), that differ in their side-chain structure only. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol [10]. Both forms effectively raise serum 25(OH)D levels [28, 31]. It appears that at nutritional doses vitamins D2

The recent increase in vitamin D interest by the general public has fuelled a big rise in sales of over-the-counter vitamin D preparations. Additionally, products with progressively increasing content of over-the-counter vitamin D preparations are becoming increasingly prevalent. Many types of pharmaceutical preparations for vitamin D supplementation are commercially available, including oily drops,

Individuals at high risk for deficiency should have a vitamin D blood test first; a dosage of up to 3000–4000 IU may be required to restore blood concentrations. In the Middle East and African countries, vitamin D doses ≥2000 IU/day may be

Whilst for pregnant women and children (1000 IU daily is safe) [33], there are very few concerns regarding vitamin D complications; in the elderly and especially those who are vitamin D replete, there has been some concerns about increased falling risks (especially at high doses) [34]. A 1-year, double-blind, randomised clinical trial conducted in Switzerland of 200 community-dwelling men and women 70 years and older with a prior fall, randomised to receiving monthly 24,000 IU (low-dose), 60,000 IU of vitamin D3 and 24,000 IU of vitamin D3 plus 300 μg of calcifediol, found that the higher-dose groups increased vitamin D levels more effectively but did not improve lower extremity function (over 12 months) and indeed increased fall incidence slightly [35]. Whilst this is not a cause for alarm, the study does confirm the popular scientific idiom 'Too much of a good thing is bad thing'. Bischoff-Ferrari [36] advocates against regular high-dose bolus or monthly moderate doses of vitamin D for fracture prevention. Indeed Zhao [5] in a metaanalysis of 33 randomised trials involving 51,145 participants found no benefit of supplements containing calcium, vitamin D or both compared with places in fracture prevention among community-dwelling older adults (over 50 years); however, it is noted that the research is limited by the lack of reporting of whether participants had osteoporosis, osteopenia or low bone mass, as well as participants

In contrast, research on vitamin D replenishment in the mild to moderate vitamin D-deficient elderly population following a hip fracture showed that a single loading dose of cholecalciferol (250,000 IU vitamin D3, the REVITAHIP (Replenishment of Vitamin D in Hip Fracture) strategy) or placebo, both receiving daily vitamin D (800 IU) and calcium (500 mg), was able to improve vitamin D levels and reduce falls (**Figure 3**) and pain levels [14]. The REVITAHIP investigators adopted a similar loading dose vitamin D followed by maintenance vitamin D at 800 IU (and calcium) daily supplied to the participants, due to the very high rates of vitamin D deficiency noted in the HORIZON Recurrent Fracture study (observed in the first 385 patients [37]). The investigators found that virtually all participants in the active treatment group reached target vitamin D (>50 nmol/L) at weeks 2 and

Interestingly, Smith [38], in a group of elderly women (mean age 66 years) with hypovitaminosis D (<50 nmol/L), demonstrated that vitamin D followed

and D3 are equivalent, but at high doses vitamin D2 is less potent.

needed to reach the target 25(OH)D level ≥20 ng/ml [32].

mainly from Europe and the United States.

4 compared with the placebo group (**Figure 4**).

**100**

*REVITAHIP Active Vitamin D Protocol (initial 250,000 IU followed by 800 IU Vitamin D3 and 500 mg Calcium Daily at 4 weeks shows significance in reducing falls.*

#### **Figure 4.**

*REVITAHIP Active Vitamin D Protocol (initial 250,000 IU followed by 800 IU Vitamin D3 and 500 mg Calcium Daily at 2, 4 and 26 weeks showed significant 25-OHD levels improvements compared with the placebo group.*

a U-shaped curve on falls whether analysed by serum dose or serum 25(OH)D3 levels. The investigators found no decrease in the incidence of falls on low vitamin D doses (400, 800 IU), a significant decrease in falls on medium doses (1600, 2400, 3200 IU) (p = 0.020). Counterintuitively, Smith found no decrease on high doses (4000, 4800 IU) compared to placebo (p = 0.55). The rate of falls was 60% in the lowest quintile <25 ng/ml (<50 nmol/L), 21% in the low middle quintile 32–38 ng/ ml (80–95 nmol/L), 72% in the high middle quintile 38–46 ng/ml (95–115 nmol/L) and 45% in the highest quintile 46–66 ng/ml (115–165 nmol/L). A similar U-shaped pattern in the subgroup with a previous fall history was noted among the quintiles of 25(OH)D3 levels (**Figure 5**, [38]).

Conglomerating the results from Bischoff-Ferrari, Lyles, Smith and Mak, there does not appear to be any justification in having regular high-dose vitamin D supplements at monthly intervals, due to the risk of vitamin D toxicity, hypercalcaemia and perhaps oversaturation of vitamin D receptors on skeletal muscles, leading to a propensity to falls. The author would recommend the REVITAHIP strategy of initial single loading dose bolus (250,000 IU) followed by regular 800 IU daily [14, 37], or 24,000 IU monthly [35], supplementation but would recommend to be cautious with the Smith approach of medium daily dosages, probably up to 1600 IU daily without a bolus [38], for high-risk populations, and would support that larger monthly doses of 100,000 IU need further evaluation with respect to efficacy and safety.

#### **Figure 5.**

*The rate of falls was 60% in the lowest quintile <25 ng/ml (<50 nmol/L), 21% in the low-middle quintile 32-38 ng/ml (80-95 nmo/L), 72% in the high middle quintile 38-46 ng/ml (95-115 nmo/L) and 45% in the highest quintile 46-66 ng/ml (115-165 nmol/L). A similar U-shaped pattern in the subgroup with a previous falls history was noted amongst the quintiles of 25(OH)D3 levels [38].*

### **8. Conclusions**

Vitamin D is an essential fat-soluble hormone with multiple positive pleiotropic effects on the human bodies besides the optimisation on bone health. The evidence for ensuring high-risk groups such as pregnant women, children and those from the Middle East and African countries is vitamin D replete with either dietary, sunlight or combination with appropriate vitamin D supplements at moderate doses. For community-dwelling older adults with a history of falls, osteoporosis and/or fractures, there is still evidence for a good safety profile for moderate dosages (either through an initial single-dose bolus followed by daily low-dose or regular moderate daily or monthly dosages). The author does not recommend regular high-dose bolus (>500,000 IU bolus) or greater than 50,000 IU monthly given its possible increased risk of falls and associated fractures.

## **Author Note**

The author dedicates this chapter to his eldest son Johann, for his constant bravery, courage, diligence and dedication to his sport, studies and in life, and to his mother Demi, for her constant reminder to strive for perfection.

**103**

**Author details**

Jenson Mak1,2

*An Evidence-Based Review of Efficacy and Safety of Dietary, Natural Supplements…*

1 John Walsh Centre for Rehabilitation Research, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Healthy Ageing - Mind & Body - Vitality, NSW, Australia

\*Address all correspondence to: jenson.mak@gmail.com

provided the original work is properly cited.

*DOI: http://dx.doi.org/10.5772/intechopen.89598*

*An Evidence-Based Review of Efficacy and Safety of Dietary, Natural Supplements… DOI: http://dx.doi.org/10.5772/intechopen.89598*
