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Name : Cherilyn Herbert

Student Number : 13200152

Title of Article critique : Calcium plus Vitamin D Supplementation and the Risk of Fractures

Authors :

Title of Journal : The New England Journal of Medicine

Volume : 354

Issue : 7

Year : 2006

Pages : 669-683

Literature Review

There have been various studies performed from 1990-2006 of the effects of calcium plus vitamin D supplemental therapies on fractures.

A 2 year study was conducted from February 1st 1999 to March 31st 2002 5292 participants were recruited across 21 hospitals in the UK and randomly allocated to four equal groups receiving 800 IU vitamin D3,1000mg calcium, vitamin D3 (8000 IU) combined with calcium (1000mg), or a placebo. Data was collected by postal questionnaire every 4 months with dietary intake of calcium and vitamin D monitored along with sun exposure. Time interval for follow up was between 24 and 62 months. There was difficulty with compliance concerning the allocated tablets as most patients were above the age of 70 limiting cognitive function as well as gastrointestinal complaints. This study measured dietary intake and sun exposure however participants above the age of 70 have a higher incidence of fractures form falls. Participants receiving supplemental therapy of intake of more than 200 IU vitamin D or more than 500 mg calcium supplements in the past 5 years were excluded. (Grant A.M., Anderson F.H., Avenell A.,Campbell M.K, Cooper C.,
 Donaldson C., Francis M.R., Gillespie W.J., Robinson C.M., TorgersonD.J., &Wallace W.A.,2005).

In another study, there only female participants randomized into groups of 4 receiving injectable vitamin D2, oral vitamin D3 and calcium. A placebo was not used and patients were seen 3,6,12 months post fracture. Participants were recruited post surgery after suffering a hip fracture and had to undergo mental tests. Falls were not measured during the study. Bone density of patients were measured prior to study and repeated after 12 months. The study demonstrated that injectable vitamin D3 were easier to allocate particularly in elderly patients, however oral calcium and vitamin D3 were more effective as patients receiving injectables were deficient in vitamin D. (Armas LA, Hollis BW, Heaney RP 2004).

A study done for 3 years from October 1983 to April 1986 66 postmenopausal women participated in a double blind, randomized and placebo controlled study. Dietary intake of calcium was not recorded in this study. In the 150 week period in which the study was conducted there was a 13 week period in which no drugs were received. Timing of the vitamin D, calcium supplements or placebo were allocated in the morning and afternoon with specifications to consume with water. Height and urine of participants were measured. The study concluded that bone mineral density increased significantly. (Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH 1990).

In another study in 2002 women were also used in a randomized, double blind study. The 48 participants were categorized into 2 groups supplementation with calcium and vitamin D or placebo or just calcium alone. A bio-phosphate alendronate was also used as it reduces bone mineral loss. The study was done for just 2 months with blood and urine samples collected after 15,30 and 90 days of treatment. Inclusion criteria were low bone mineral density and dietary calcium intake. The study showed that alendronate along with supplementation of calcium and vitamin D produced marked changes in bone mass. Parathyroid hormone levels is demonstrated to be modified following supplementation with vitamin D and calcium in these studies. However in this study this may not have been shown as alendronate increases this hormone. The study lacked a control group, a small number of participants and no measurements of bone densities. No follow up study was performed but study concluded that combined treatment would be beneficial. (Michel Brazier, S. Kamel, F. Lorget, M. Maamer, C. Tavera, N. Heurtebize, F. Grados,M. Mathieu, M. Garabedian,J.L. Sebert and P. Fardellone ,2002).

This randomized placebo controlled study was performed for 3 years with 295 men and women previously receiving supplementation of 500 mg of Calcium and 700 IU of Vitamin D. These participants with no history of disease or prior use of supplementation to aid bone metabolism were followed up for 2 years with no use of supplements. Physical activity was also measured. The study found during the intervention there was no significant rise of dietary intake of calcium and vitamin D but the intakes rose during the follow up period. The study was overall weak in studying the effects of discontinued therapy on fractures. Men did display improved bone mineral density however this was attributed to increased levels of estrogen concentrations in the body that may enhance use of dietary calcium. 13 women were also found to have non-vertebral fractures during the follow up study.( Dawson-Hughes B., Harris S., Krall E.A.,& Dallal G.E ,2000).

Most studies favored female participants as well as being randomized and placebo controlled. Length of time in which the study was conducted was also beneficial in producing the positive effects of supplementation. The studies had a large number of participants and thus data was collected via questionnaire.

The Critique

Summary

Rebecca (2006), in a double blind study recruited 36,282 postmenopausal women of 50-79 years of age who were currently enrolled under the Women’s Health Initiative (WHI) trial. Participants received 1000 mg of calcium carbonate with 400 IU of vitamin D daily or a placebo and were allowed personal supplementation during the time in which the trial was conducted.

Bone mineral density was measured in the vitamin D and calcium group and risks of fractures were determined by questionnaires, interviews and examinations. Blood analysis was investigated to measure 25-hydroxyvitamin D levels pre-randomization. Subjects who were compliant with their supplementation of up to 80% reported a 29% reduction in hip fractures.
Therapy of calcium and vitamin D increased bone mineral density of the hip however, a 12% reduction in the rate of hip fracture in this group was not statistically significant. Total reductions in spinal and total body fractures were also non-significant in group receiving supplementation versus the placebo. Vitamin D was also lower in dosage compared with previous trials performed. It was mentioned that for greater fracture reduction higher doses of vitamin D are required in this study.

Collation of data was positive as shown in Figure 3 with an in-depth questionnaire used for participants. Linear regression was used as shown in Figure 2 to draw comparisons of bone mineral densities. However number of participants decreased during sample sizes which would limit p value significance.

Compliance of the subjects were positive at 76% still taking the pills however by the end of the trial only 59% were taking the appropriate dosage. Women who were vitamin D deficient also failed to confirm the benefit of receiving vitamin D therapy with reduced fracture rates. It has showed that women receiving vitamin D and calcium supplementation had greater preservations of total hip bone density but did not significantly reduce incidence of fractures.

Strengths

The study utilized evidence tables and in-depth questionnaires that obtained physical activity levels, ethnicities, smoking history, as well as extra supplementation used during the trial. Advisement during the trial was also good as subjects were advised to take supplements with meals to maximize absorption and exclusion criteria was better in comparisons with previous trials. 25-dihydroxyvitamin D levels were also measured for all groups including the placebo up to 2 years after randomization of the trial. Data and follow up interventions were done well by clinic visits with 6 months intervals and adherence of supplements were improved with weighing of returned pill bottles.

It had been reported in previous studies that gastrointestinal symptoms occur during trial and subjects in this study were not excluded but had their dosage adjusted. This was performed without unblinding. Fractures were also not limited to just hip and vertebrae but included those of the ribs, skull face and more. Fractures were also verified and not just by questionnaire but by medical imaging. The study was also strengthened by blinded adjudicators for final adjudication of hip fractures and this agreement equaled at 94%. Analysis of vitamin D levels were done by fasting blood levels analysis and control group had no incidence of fractures during the duration of the study. In order to determine the true fracture reduction potential of vitamin D levels had to be ascertained prior to the study and this was performed. During assessment of effects of calcium and vitamin D on risk of fractures along with different risk factors of subjects, the same Cox proportional-hazards models were extended and this will increase validity.

Data was also censored during the study when subjects increased the use of osteoporosis medications. Solar irradiance was also measured by region and this is significant as a substantial amount of vitamin D is formed on the skin. Overall the study was well presented with protocols adhered to strictly and assessment of subjects by questionnaires and follow up were consistent and reliable.

Weaknesses

The research done during this study did not provide any new scientific breakthroughs and was merely observational. The large number of subjects in the cohort n= 36,282 also decreased compliancy and there was no evaluation to prove that subjects had reached a therapeutic dose level of vitamin D. In other previous studies, appropriate vitamin D blood levels were determined and set at 32ng/mol. A baseline should have been set up with only including subjects who achieve levels above 32ng/mol in calculations of fracture reduction.( Grant A.M., Anderson F.H., Avenell A.,Campbell M.K, Cooper C.,
 Donaldson C., Francis M.R., Gillespie W.J., Robinson C.M., TorgersonD.J., &Wallace W.A ,2005). This trial study also failed to demonstrate which type of Vitamin D was used which was either D2 or D3. This is significant as previous research has clarified that Vitamin D3 is the preferred form of Vitamin D as it is 3 times more potent than Vitamin D2.(Armas L, Hollis B.,Hearney P, 2004).

This WHI trial has been poorly designed despite being long-term and using a large cohort. This is because the vitamin D intervention used at 400 IU daily was too low. A study in 2005 clearly showed that 400 IU had no significant effect on fracture incidence and this was clearly documented yet WHI still published its findings. During the trial use of calcium and vitamin D increased the risk of renal calculi by 17% more than the placebo and the study’s exclusion criteria were subjects with incidence of renal calculi. Nutrient intakes of subjects also need to measured as intakes could pose changes in clinical outcomes of the study. Women need to be absent in anemia in this case. Reliable biomarkers need to be identified in this study to fulfill the dose response relationship such as osteocalcin measuring bone turnover index. This is used as an intermediate marker for fractures in the body.( Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA ,1999).

Results of the studies concerning 25-hydroxyvitamin D concentration and calcium and vitamin D intake could have been presented graphically to show dose relationship between exposure and outcome.

Conclusions drawn in this study are reliable as the trial reported it could not separate the independent effects of calcium and vitamin D. The study could have been improved by not allowing extra supplementation of multivitamins. Primary and secondary outcomes of this intervention study were also established.

Future Directions

The current meta-analysis of vitamin D and calcium supplementation greatly expands on research done by WHI. Dosage of vitamin D needs to be increased in further research with a minimum of 800IU. A recent study done by the WHI study provides a the link between low vitamin D levels and hip fractures. In this case-controlled study of the, women with the lowest levels of vitamin D (less than 19 ng/mol) were found to have a 77% higher risk of hip fracture than women with the highest vitamin D level (average 28 ng/ mol). To further increase effectiveness of vitamin D levels adherence needs to be strict and dosage regime needs to be followed and to potentially demonstrate a benefit doses need to be taken over a longer period of time. Further research also needs to be directed if vitamin D is effective alone without calcium.

Conclusion

Based on the studies done and the WHI trial it can be concluded that routine use of calcium plus vitamin D supplementation at set dosages especially at 800 IU for vitamin D among postmenopausal women can improve the risks for fracture. A cause and effect relationship can be seen establishing that calcium with vitamin D or vitamin D alone can reduce the loss of bone mineral density. Improving bone mineral density loss may contribute towards a reduction in the risk of fractures. Target groups should be also aimed and maintained at postmenopausal women above the age of 50 years. There is significant need for biochemical markers and supplementation be tailored towards an individual in order to see positive responses.

References

1. Armas LA, Hollis BW, Heaney RP,(2004). Vitamin D2 is much less effective than vitamin D3 in humans. Journal of Clinical Endocrinology & Metabolism, 89(11),5387-5391

2. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E., Dietrich T., Dawson-Hughes B.,(2005). Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. The Journal of the American Medical Association 293(18), 2257-2264. doi:10.1001/jama.293.18.2257 3. Bucher HC, Guyatt GH, Cook DJ, Holbrook A, McAlister FA.(1999). Users' guides to the medical literature: XIX. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group. The Journal of the American Medical Association, 282(8),771-778. doi:10.1001/jama.282.8.771

4. Cauley JA, LaCroix A, Wu L, et al.(2007). Serum 25 hydroxy vitamin D 25(OH) and the risk of hip fractures: The Women’s Health Initiative (WHI). Presentation 1202; 29th Annual Meeting of ASBMR; Honolulu

5. Dawson-Hughes B., Harris S., Krall E.A.,& Dallal G.E,(2000) Effect of withdrawal of calcium and vitamin D supplements on bone mass in elderly men and women. American Journal of Clinical Nutrition, 72(3),745-750

6. Grant A.M., Anderson F.H., Avenell A.,Campbell M.K, Cooper C.,
 Donaldson C., Francis M.R., Gillespie W.J., Robinson C.M., TorgersonD.J., &Wallace W.A.(2005). Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. The Lancet, 365(9471), 1621-1628 doi:10.1016/S0140-6736(05)63013-9

7. Michel Brazier, S. Kamel, F. Lorget, M. Maamer, C. Tavera, N. Heurtebize, F. Grados,M. Mathieu, M. Garabedian,J.L. Sebert and P. Fardellone( 2002). Biological Effects of Supplementation with Vitamin D and Calcium in Postmenopausal Women with Low Bone Mass Receiving Alendronate. Clinical Drug Investment, 22 (12),849-857

8. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH (1990). Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. New England Journal Of Medicine, 322(18),1265-1271.

9. HARWOOD R.H., SAHOTA O., GAYNOR K., MASUD T.,. HOSKING D.J.(2004). A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. British Geriatrics Society, 33(1),45-51.

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