File Name: vitamin d and bone health .zip
Osteoporosis is associated with increased morbidity, mortality and significant economic and health costs.
- Vitamin D and Bone Health
- Too much vitamin D may harm bones, not help
- Vitamin D and Bone Health
- Vitamin D and Bone Health; Potential Mechanisms
Vitamin D and Bone Health
Osteoporosis is associated with increased morbidity, mortality and significant economic and health costs. Vitamin D is a secosteriod hormone essential for calcium absorption and bone mineralization which is positively associated with bone mineral density [BMD].
It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. Sub-optimal vitamin D status has been reported in many populations but it is a particular concern in older people; thus there is clearly a need for effective strategies to optimise bone health.
A number of recent studies have suggested that the role of vitamin D in preventing fractures may be via its mediating effects on muscle function a defect in muscle function is one of the classical signs of rickets and inflammation.
Studies have demonstrated that vitamin D supplementation can improve muscle strength which in turn contributes to a decrease in incidence of falls, one of the largest contributors to fracture incidence.
Osteoporosis is often considered to be an inflammatory condition and pro-inflammatory cytokines have been associated with increased bone metabolism. The immunoregulatory mechanisms of vitamin D may thus modulate the effect of these cytokines on bone health and subsequent fracture risk. Vitamin D, therefore, may influence fracture risk via a number of different mechanisms. For the majority of the population the principle source of vitamin D is synthesis following exposure of the skin to UVB radiation [ nm] [ 1 ].
UVB radiation acts in the upper epidermis of the skin with 7-dehydrocholestrol converted to pre-vitamin D3 by photolysis of the B ring structure followed by isomerisation [ 1 ]. These structural modifications mean that the molecule no longer conforms within the plasma membrane and is ejected into the extra-cellular space and drawn into the capillary beds where it is bound by the vitamin D binding protein [DBP] and transported to the liver [ 1 ].
Further UVB exposure results in the formation of in-active photoproducts such as tachysterol and lumisterol that have negligible effects on calcium metabolism [ 4 ] and prevent vitamin D toxicity from sun exposure. Geographical location is a key determinant of the efficiency of vitamin D synthesis as production is dependent on the angle of sunlight or the solar zenith angle [ 5 ].
Synthesis can also be affected by lifestyle, environmental, and physiological factors. Lifestyle factors such as the use of sun-screen, time spent outside and wearing of clothing significantly affect UVB exposure as do environmental factors such as pollution, cloud cover and ozone presence [ 6 , 7 , 8 ].
Physiological differences such as skin complexion and age also affect synthesis: darker skin has significantly higher melanin content and subsequently requires a higher UVB exposure time than paler skin to synthesize an equivalent amount of vitamin D [ 10 ].
Increasing age is associated with a significant decrease in the amount of 7-dehydrocholesterol in the skin and thus, a reduction in vitamin D synthesis with studies reporting up to four times less cutaneous synthesis in adults aged over 70 years compared to a 20 year old adult [ 11 ]. Vitamin D is also obtained to a limited extent from the diet, albeit few dietary sources naturally contain the vitamin in sufficient quantities to make a significant contribution to requirements.
The two main vitamin D secosteroids within the diet are vitamin D2 [ergocalciferol] and vitamin D3 [cholecalciferol]. Vitamin D2 is derived from plant and fungi and is produced through the irradiation of ergosterol. Vitamin D3, as previously mentioned, is produced from 7-dehydrocholesterol and is obtained in the diet from animal products with oily fish, fish oils, eggs and dairy produce providing the best dietary sources.
A recent double blind, placebo controlled study reported that there is no significant difference in the effectiveness of the two isomers [ 12 ]; however it is more often reported that vitamin D3 is the more effective.
This higher effectiveness of vitamin D3 over D2 is owing to a possible increased affinity for the vitamin D binding protein [DBP] [ 13 , 14 ] leading to a reduction in clearance of D3 and providing longer lasting concentrations of 25 OH D in the blood than D2 [ 14 ]. In relation to intakes, the composition of the habitual diet will impact on vitamin D status.
For example, within Ireland the majority of vitamin D intakes are from sources such as meat and meat products [ 15 ] which contain low concentrations of the vitamin. Rich food sources such as oily fish are consumed infrequently. Few vitamin D fortified foods, aside from margarine, are available within Western Europe possibly owing to early adverse advent incidents of infantile hypercalcaemia attributed to over-fortification of dried milk with vitamin D [ 16 ].
Other countries, including the USA fortify foods; however, surveys have suggested significant differences between the actual and reported levels of fortification [ 17 , 18 ]. Vitamin D absorption occurs in the ileum and jejunum. Vitamin D is bound by the DBP and transported to the liver [ 1 ]. Excess non-hydroxylated vitamin D is stored in the liver, adipose tissue and muscle [ 24 ]. The kidney however, is not the only source of CYP27B1: it has also been detected in tissues such as the colon, brain and pancreas suggesting different autocrine functions of the hormone [ 25 ].
Once the hormone has been metabolized it is converted to calcitroic acid and excreted. The primary effect of vitamin D is enhanced calcium absorption in the small intestine [ 23 , 24 , 25 ]. The hormone interacts with the vitamin D receptor [VDR] in intestinal cells and complexes with the retinoic acid x receptor [RXR] in the nucleus [ 23 , 24 ]. This complex binds to the vitamin-D-responsive element [VDRE] of the calcium channel [TRPV6] which increases uptake of calcium into the cells and increases the absorption of calcium [ 24 , 25 ].
This conversion releases chemicals such as hydrochloric acid to metabolise calcium stores from the bones into circulation to maintain the optimal physiological range [ 25 ]. Until recently, it was generally assumed that enough vitamin D was synthesized from sun exposure to meet requirements and no recommendations for dietary intakes for adults aged yrs were set.
However, research highlighting the effects of low vitamin D status [ 26 , 27 ] has indicated the importance of vitamin D in the diet. The difficulty in assigning a RNI for vitamin D intake is exacerbated by the current lack of agreement on optimal vitamin D status. Over extended periods of time, insufficiency has been associated with increased bone loss and secondary hyperparathyroidism leading to increased fracture risk [ 36 ].
Sufficiency has been regarded as the point at which further intakes will have no additional beneficial effects on PTH and calcium metabolism in regard to bone health.
However, the cut-off values for sufficiency are still under debate. As mentioned earlier, the dietary intake of vitamin D required to prevent vitamin D deficiency and ensure optimal vitamin D status will vary depending on sun exposure preferences. However, the authors also calculated that a dietary intake of Such intakes are considerably higher than estimated vitamin D intakes in Ireland [3.
Vitamin D toxicity is rare [ 45 ]. The symptoms include vomiting, nausea, constipation, weight loss, weakness and kidney stones with subsequent hypercalcaemia and ectopic calcification of soft tissue [ 46 ].
However, as discussed earlier, the formation of vitamin D from sunlight is a self-limiting reaction; thus preventing toxicity from sun exposure. Peak bone mass is attained by the third decade of life [ 50 ] with genetics, physical activity, nutrition and lifestyle factors [ 51 , 52 ] playing key roles in the accumulation and maintenance of bone.
Age related bone loss occurs around the fourth decade [ 53 ], resulting in a gradual decline of BMD though this process is accelerated in females during and up to 10 years post-menopause owing to possible oestrogen deficiency derived bone loss [ 54 ]. The development of bone disease in later life is related to the attainment of maximum peak bone mass and the maintenance of bone mass in adulthood [ 55 ].
In relation to vitamin D, research has shown that inadequate vitamin D intakes over long periods of time can lead to bone demineralization [ 56 ]. Vitamin D deficiency leads to decreased calcium absorption and ultimately the release of calcium from the bones in order to maintain circulating calcium concentrations [ 56 ]. Continuous bone turnover and resorption weakens the architecture of bones and increases fracture risk via secondary hyperparathyroidism [ 56 ] ultimately leading to the development of osteomalacia and osteoporosis.
Osteoporosis is clinically defined as a BMD 2. There is a direct relationship between BMD and fracture risk [ 59 ], with a decrease in bone strength and density associated with an increased incidence rate of fractures [ 60 ]. Fractures usually occur at the hip, spine and wrist [ 61 ] and not only carry considerable health costs, but can also result in increased mortality and a decreased quality of life [ 62 , 63 , 64 ].
Fracture incidence has been shown to increase with age [ 65 ]; therefore it has been imperative to develop preventive strategies in order to minimize the development of this condition. Given the relationship between vitamin D and bone mineralization, optimal vitamin D status is essential for minimization of fracture risk. A number of studies have investigated the effects of vitamin D or vitamin D in combination with calcium on fracture incidence Table 1 , Table 2 , Table 3.
Three intervention trials of vitamin D alone [ 66 , 75 , 77 ] have reported a significant reduction in fracture occurrence. While in another intervention [ 66 ], which supplemented with ,, IU D2, an apparent significant fracture reduction from baseline was reported, especially in the upper limb both in free-living and institutionalized subjects [though this study had no placebo and was not blinded]. These results are also supported by trials with vitamin D in combination with calcium.
For example, in one study [ 89 ], supplementation with IU D3 and calcium resulted in a reduction in the fracture incidence rate of community dwelling individuals. Furthermore, another trial [ 81 ] reported a significant reduction in hip fractures among institutionalized elderly females supplemented with calcium and vitamin D3 for two years.
A subsequent analysis of the same cohort after 42 months supplementation indicated that hip fractures and non-vertebral fractures remained lower in the treatment group [ 94 ]. However, not all trials of vitamin D or vitamin D in combination with calcium have reported significant effects.
For example, Lyons et al. U D2 quarterly for five years and reported no significant reduction in fractures. The difference in outcomes between trials is difficult to explain, albeit there are a number of possible explanations for lack of reported effects.
A large number of trials [ 69 , 71 , 74 , 76 , 85 , 87 , 88 , 91 , 92 , 93 ] have supplemented with between IU vitamin D which may not be enough to exert a beneficial effect according to a recent meta-analysis [ 95 , 96 ]. In addition, studies which have documented significant fracture reductions have reported that effects may be more evident among institutionalized elderly people compared to free-living individuals. These observations are supported by a number of meta-analyses.
It has also been reported that vitamin D and calcium intervention is more effective in reducing the risk of hip fracture in patients in institutionalized care compared to free living individuals in the community [ 94 , 95 ] with more than IU vitamin D and more than mg calcium daily required respectively to exert a beneficial effect. Conversely, a recent Cochrane analysis concluded that vitamin D alone did not have a significant effect on fracture prevention and was only effective when combined with calcium in institutionalized individuals [ ].
The use of such analogues, however, is not widely advocated at present given the potential risks and cost implications associated with them [ 99 ]. Taken together, the results from the meta-analyses support a cause and effect relationship between vitamin D in combination with calcium in the reduction of risk of vertebral and non-vertebral osteoporotic fractures.
Several mechanisms may underlie this positive association between vitamin D and fracture risk including the well documented beneficial effects of vitamin D on bone mineral density.
A number of cross-sectional studies have investigated the relationship between vitamin D status and BMD. For example, one study [ ] of middle aged women reported that serum concentrations of 25[OH]D were positively related to bone density of the lumbar spine, neck and trochanteric regions of the femur.
Given the observed relationship between vitamin D status and BMD, a large number of intervention studies have investigated the effects of vitamin D alone or vitamin D in combination with calcium on BMD Table 4 , Table 5 , Table 6. Vitamin D alone and in combination with calcium appears to have a clear significant effect on BMD. For example, 5 out of 9 studies of vitamin D alone [ 70 , 73 , , , ], plus 16 of 22 studies [ 81 , 84 , 88 , 92 , 94 , 98 , , , , , , , , ] of vitamin D in combination with calcium have reported significant positive effects on BMD.
Supplementation with IU D2 resulted in rapid improvement in vitamin D status and significant improvement in spinal and the femoral neck BMD. The findings are supported by another trial [ ] of over elderly mobile females in whom two years of vitamin D3 supplementation resulted in significant improvements in BMD. The improvements in BMD can also be seen in the trials with vitamin D and calcium.
Over the last 20 years, 14 intervention studies examining the effect of vitamin D and calcium supplementation on BMD have been published. Overall, positive results have been reported, with doses more than IU associated with significant effects on bone heath. However, the optimal dosage of vitamin D remains unclear. Four trials have reported significant increases in BMD with IU [ 84 , ] to IU [ 81 , 88 ] D3 and calcium [, mg]; however, in a study that supplemented African-American females with IU D3 and 1,,mg of calcium [ ] no significant effects were reported.
The findings in African-American females could be explained, in part, by lower bone remodelling rates [ ] and enhanced skeletal resistance to the effects of PTH [ ] in this population group.
Studies intervening with higher doses of vitamin D have also produced conflicting results. In the latter trial, 45 elderly participants were supplemented with vitamin D3 through bread fortification. Trials Table 5 supplementing with vitamin D analogues have also reported significant improvements in BMD.
Trials [ 98 , 99 , , , , ] with vitamin D analogues and calcium have also reported consistent results with the majority reporting significant improvements in BMD [ 70 , 73 , 98 , 99 , , , , ]. In summary, the majority of vitamin D supplementation trials demonstrate a positive effect of the vitamin on BMD and in de facto fracture incidence although further studies are required to confirm the optimal dose of vitamin D associated with these benefits.
Moreover, although the potential benefits of vitamin D on fracture incidence may be at least partly attributed to beneficial effects on BMD, vitamin D may also impart advantages by reducing fracture occurrence through other mechanisms.
Too much vitamin D may harm bones, not help
Participants who received at least 1 dose of study drug and underwent at least 1 follow-up measurement were included in the primary analyses. The horizontal line in the middle of each box indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles. The horizontal line in the middle of each box left column indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles. There were no significant differences in bone strength at either the radius or tibia. Calcium supplementation was provided to participants with dietary intake of less than mg per day. Baseline, 3-month, and 3-year levels of 25 OH D were These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.
Vitamin D and Bone Health
J Am Osteopath Assoc ; 3 — Nutrients usually act in a coordinated manner in the body. Intestinal absorption and subsequent metabolism of a particular nutrient, to a certain extent, is dependent on the availability of other nutrients. Magnesium and vitamin D are 2 essential nutrients that are necessary for the physiologic functions of various organs.
Christodoulou, T. Goula, A. Ververidis, G. Vitamin D is important for normal development and maintenance of the skeleton.
Vitamin D and Bone Health; Potential Mechanisms
View the most recent version. Information identified as archived is provided for reference, research or recordkeeping purposes. It is not subject to the Government of Canada Web Standards and has not been altered or updated since it was archived. Please " contact us " to request a format other than those available. The human skeleton is constantly being restored and replaced. In growing children, bone formation exceeds bone loss. The two processes balance out in adulthood, but with advancing age, bone mass starts to decrease.
There's no question that vitamin D can help build strong bones. But there may be a sweet spot when it comes to how much. A study published in the Aug. JoAnn E. While there is no question that vitamin D and calcium are essential to bone health, it appears that very high doses of vitamin D don't provide further benefits for bone health and may actually have a harmful effect. Researchers gave more than healthy adults daily doses of international units IU , 4, IU, or 10, IU of supplemental vitamin D.
GM has been shown to influence various determinants of bone health. In animal models, probiotics prevent bone loss associated with estrogen deficiency, diabetes, or glucocorticoid treatments, by modulating both bone resorption by osteoclasts and bone formation by osteoblast. A dietary source of probiotics is fermented dairy products which can improve calcium balance, prevent secondary hyperparathyroidism, and attenuate age-related increase of bone resorption and bone loss. Additional studies are required to determine whether probiotics or any other interventions targeting GM and its metabolites may be adjuvant treatment to calcium and vitamin D or anti-osteoporotic drugs in the general management of patients with bone fragility. This is a preview of subscription content, access via your institution. Rent this article via DeepDyve. Osteoporos Int.
Current data demonstrate that vitamin D deficiency contributes to the aetiology of at least two metabolic bone diseases, osteomalacia and osteoporosis.