Vitamin D: cause or effect?
Published in Health News and Evidence
Date published: 11 February 2014
Practice points | Cause or effect? | Dealing with deficiency: what should you do? | Indications for vitamin D testing |

Summary

Vitamin D deficiency has been linked to an ever-growing list of conditions, including cardiovascular disease, dementia and cancer. However, the causal link between vitamin D and ill-health is less clear, with trial data showing mixed results.
Two new reviews analysed the data from more than 400 studies and concluded that there is little evidence vitamin D supplementation reduces the risk of cardiovascular disease, cancer or fracture in community-dwelling people. People in institutions may receive some benefit.

What does this mean for your patients?
Practice points
• Vitamin D supplementation is ineffective for disease prevention in low-risk populations
Two new reviews have concluded that vitamin D supplementation does little to alter disease severity and clinical outcomes, particularly in extra-skeletal disorders.
• Identifying severe vitamin D deficiency is important
Severe vitamin D deficiency is a serious condition; assess high-risk individuals and treat deficiency with supplementation.
• Routine testing of vitamin D levels in low-risk populations is not recommended

Advise people at low risk of deficiency to get adequate sun exposure. There is no clinical need to test routinely or to prescribe supplements for people other than those with severe deficiency.

Cause or effect?
Since vitamin D deficiency was discovered as the cause of rickets there has been a myriad of epidemiological studies that have linked low circulating levels to a growing list of conditions, including cancer, cardiovascular disease, autoimmune conditions, diabetes and dementia as well as skeletal conditions.

The implied benefit of vitamin D supplementation (i.e. if poor health is linked to low levels of vitamin D, supplements would alleviate the risk) has driven sales growth — in the US there has been a tenfold increase in vitamin D supplement sales from 2002 to 2011.

While epidemiological data link low levels of vitamin D to various conditions3 it is less clear whether this represents a causative relationship. Is vitamin D deficiency the cause or the consequence of ill-health?

Reviewing the evidence for vitamin D supplementation
Two studies published recently in The Lancet Diabetes and Endocrinology examined the evidence linking vitamin D deficiency to ill-health and whether vitamin D supplements improved health outcomes.
The studies, a systematic review of the epidemiological and trial literature and a meta-analysis of trials, both concluded that supplementation with vitamin D does little to alter disease severity and clinical outcomes.
The systematic review analysed the results of 290 prospective cohort studies and 172 randomised controlled trials.3
Overall the prospective studies confirmed the strong associations between low levels of circulating vitamin D and cardiovascular disease, glucose metabolism disorders, infectious disease, mood disorders and dementia.
Low vitamin D levels were also associated with abnormal serum lipid levels, markers of inflammation, increased weight and poor physical functioning.

Despite this, there was no evidence of a significant effect of vitamin D supplementation on any of these disorders although in older people supplementation seemed to slightly reduce all-cause mortality, but curiously this effect was only seen at low doses of supplementation.

The second study performed a trial sequential meta-analysis, a meta-analysis method to investigate whether vitamin D supplementation reduced the risk of skeletal and non-skeletal health outcomes and, importantly, to predict whether further trials investigating this question would be likely to produce different results.
The results from traditional meta analysis showed that vitamin D supplementation alone did not alter the risk ratios for cardiovascular disease, stroke, cancer or total fracture in community-dwelling individuals
Combining vitamin D supplementation with calcium did appear to reduce the risk of hip fracture in people residing in institutions.

There also appeared to be a small positive but uncertain effect of supplementation on all-cause mortality, which supports the finding from the systematic review.

The sequential analysis showed that all endpoints fell below the futility threshold, the threshold where further research may potentially change the results of the meta-analysis. This indicates the body of evidence is sufficiently large so that any further study is unlikely to find a positive effect sufficient to change the conclusion

Limitations in the analysis
Both studies highlighted limitations to their analysis, the main one being variable quality in study design, including differences in reporting, controlling for confounders and comparing outcomes that are primary versus secondary.

The end of supplementation?
One of the possible reasons that these reviews failed to find a positive relationship between vitamin D supplementation and risk reduction could be that vitamin D insufficiency is a consequence and not a cause of ill-health.
In this case, correcting vitamin D levels would not be expected to correct the underlying pathology and therefore have little benefit.

The authors of the sequential meta-analysis concluded that, ‘there is little justification for prescribing vitamin D supplementation to prevent myocardial infarction or ischaemic heart disease, cancer or fractures, or reduce the risk of death in community-dwelling individuals.’

However, for people with moderate to severe deficiency, is supplementation still justified?

Dealing with deficiency: what should you do?
While there may be controversy regarding the role of vitamin D supplementation in the prevention of many extra-skeletal conditions, severe vitamin D deficiency affects around 4% of the population and remains a serious problem that has been shown to lead to various skeletal disorders, including osteomalacia and rickets.

Severe deficiency should be identified and treated with supplementation. Guidelines suggest using 3000–5000 IU daily for 8–12 weeks followed by ongoing treatment with 1000–2000 IU per day for moderate to severe deficiency.

It is recommended that only people at high risk of deficiency be tested (see box below); routine vitamin D testing is not recommended.
The Royal College of Pathologists of Australia state in their 2013 position statement on vitamin D testing that:

• in individuals at risk of vitamin D deficiency, measurement of 25(OH)D is an appropriate case-finding strategy

• routine screening of adults (including pregnant women), healthy infants and children for vitamin D deficiency is not currently recommended.

For most people the main source of vitamin D should be sunlight. For people with moderately fair skin, as little as 7 minutes in mid-morning summer sun may be adequate and, depending on latitude, around 7–40 minutes of exposure in winter.

Indications for vitamin D testing
People at high risk of vitamin D deficiency

• Older or disabled people in residential care
• Housebound individuals
• Dark-skinned people, particularly if modest dress is worn
• People with a disability or chronic disease
• Fair-skinned people who avoid sun exposure
• People who are obese
• People working in an enclosed environment, including nightshift workers and factory workers

Initial testing of vitamin D status in adult patients
• Signs or symptoms of osteoporosis or osteomalacia
• Increased alkaline phosphatase with otherwise normal LFTs
• Hyperparathyroidism, hypo- or hypercalcaemia or hypophosphataemia
• Malabsorption (e.g. cystic fibrosis, short bowel syndrome, inflammatory bowel disease)
• Medications known to decrease vitamin D levels (such as anticonvulsants)
• Chronic kidney failure and kidney transplant recipients.

Ref: NATIONAL PRESCRIBING SERVICE-AUSTRALIA.

G Mohan.