The recent study by Bolland and colleagues published in the Lancet Diabetes Endocrinology (Oct 4, 2018) is an updated meta-analysis that evaluated the effects of vitamin D supplementation on fractures, falls and bone mineral density (BMD) in adults. This study analyzed the pooled findings of 81 randomized control trials, collectively involving more than 50,000 participants.

The majority of the trials included in this analysis were of vitamin D alone, with daily doses of more than 800 IU daily, vs. untreated controls, in community-dwelling women age 65-years or older. Trials of high-dose vs. low-dose vitamin D, as well as co-administration of calcium with vitamin D were also included. Study duration was 1 year or less. The primary outcomes were fractures and falls; and the secondary outcome was change in BMD from baseline at the lumbar spine, total hip, femoral neck, total body, and forearm (1).

This meta-analysis found that vitamin D supplementation did not have an effect on the risk of fractures or falls, and there were no meaningful effects on BMD. The authors also concluded that there were no differences between the effects of higher and lower doses of vitamin D (1).

In more than half of the trials, subjects had a baseline vitamin D level (25OHD) of <50 nmol/L (a cutoff considered by many including the Endocrine Society (2) to indicate vitamin D insufficiency), and almost all had a baseline 25OHD <75 nmol/L. Only four trials (6%) studied people with vitamin D deficiency (25OHD <25 nmol/L), in whom vitamin D supplementation may produce different results. Since there is large variability in how vitamin D levels respond to fixed doses of vitamin D (most studies used 1000 IU per day or less), 25OHD levels may not have reached the target range of interest in these studies. The finding that vitamin D alone may not prevent fractures, falls or improve BMD is consistent with prior published studies. While studies have shown little impact on outcomes when vitamin D or calcium are used separately, a review of trials of calcium and vitamin D used together in individuals living in long-term care showed benefit (3). The current meta-analysis by Bolland included only 20 trials (25%) of vitamin D taken with calcium vs. calcium alone, and did not include studies that compared vitamin D used together with calcium vs. no treatment. Although the major strength of the current study lies in the large number of studies included in the analysis, it is important to recognize potential limitations including the heterogeneity of populations, study designs and results of the studies in the meta-analysis. Importantly, this study did not specifically address the vitamin D requirements of individuals with osteoporosis, those with risk factors for osteoporotic fractures, or those with risk factors for vitamin D deficiency. It is important to remember that vitamin D is needed for optimal calcium absorption from the gut, and plays an important role in calcium balance and bone mineralization. Inadequate vitamin D can result in poor bone mineralization, as well as bone loss due to a rise in parathyroid hormone levels. Although this study suggests that routine vitamin D supplementation, in particular, high dose vitamin D, may not be necessary for healthy individuals in the general population, these findings cannot be applied to people with osteoporosis, or to those with risk factors for fractures or vitamin D deficiency. Osteoporosis Canada recommends that individuals with osteoporosis or with risk factors for fractures receive adequate vitamin D, as recommended at 800-2000 IU per day (4), however vitamin D dosing may require adjustment in order to achieve the adequate 25OHD level needed for optimal calcium homeostasis. Further studies are needed to clarify the optimal 25OHD level for those with osteoporosis or with risk factors for fracture. High dose vitamin D supplementation should be avoided due to potential harms (5). There are large randomized trials currently ongoing to help answer questions about effects of vitamin D supplementation on other aspects of health (6). Appropriate osteoporosis medication may be required for those at high fracture risk. It is important to note that clinical trials showing the effectiveness of osteoporosis medications all included vitamin D and calcium as part of the treatment regimen. References: 1. Bolland et al Lancet Diabetes Endocrinol Oct 2018 2. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. Michael F. Holick et al The Journal of Clinical Endocrinology & Metabolism, 2011 96 (7): 1911-1930. 3. Papaioannou et al CMAJ 2015 187: 1-11. 4. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada by David A. Hanley MD et al CMAJ 2010 5. Smith et al 2017 J Steroid Biochem Mol Biol173:317-22 6. Pradhan AD Manson JE Update on the Vitamin D and OmegA-3 trial (VITAL). Study J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):252-6. 7. Manson JE et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2018 Nov 10; [e-pub]. (https://doi.org/10.1056/NEJMoa1809944) Prepared by Aliya Khan, Sandra Kim, Rowena Ridout and Lianne Tile, on behalf of the Scientific Advisory Council of Osteoporosis Canada, Rapid Response Committee.

Osteoporosis Canada’s overall position statement in response to this study:

This study did not specifically address the vitamin D requirements of individuals with osteoporosis, those with risk factors for osteoporotic fractures, or those with risk factors for vitamin D deficiency. Vitamin D is needed for optimal calcium absorption from the gut, and plays an important role in calcium balance and bone mineralization. Osteoporosis Canada recommends that individuals with osteoporosis or with risk factors for fractures receive adequate vitamin D, as recommended at 800-2,000 IU per day.

A recent article on the effect of vitamin D supplementation on fractures, falls and bone mineral density was published in the journal Lancet Diabetes Endocrinology by Bolland and colleagues (October 4, 2018). This research reviewed the available literature as part of a systematic review and meta-analysis. A systematic review is a research method used to thoroughly locate and synthesize all the information (evidence) related to a specific topic. A meta-analysis uses statistical tools to combine data from the studies included in the review to provide an overall finding. During the systematic review process, it is important that the researchers combine studies that are clinically and statistically similar. This research summarized and combined the results of 81 randomized controlled trials, in which more than 50,000 people were enrolled.

There are some noteworthy characteristics of the included 81 studies. For example, the majority of studies were done in community-dwelling women age 65 years or older, and the only “intervention” was vitamin D in doses of more than 800 IU/day. There were also studies of higher dose vs. lower dose vitamin D, as well as studies that included calcium and vitamin D given together. The studies in the review were based on participants taking vitamin D for one year, or less. The main focus of the systematic review was to look at the effect of vitamin D on fractures and falls. However, there was also a summary of the effect of vitamin D on the change in bone mineral density [from the start of the study (baseline) to the final assessment] (1).

Based on the results of the meta-analysis, the authors reported that vitamin D supplementation did not have an effect on the risk of fractures or falls, and that there were no meaningful effects on participants’ bone mineral density. The authors also concluded that there were no differences between the effects of taking higher and lower doses of vitamin D (1) for these health outcomes.

There are several factors that should be considered when reviewing these results. First, in more than half of the studies, participants had a baseline vitamin D level (25OHD – the blood test used to measure Vitamin D levels in the blood) of less than 50 nmol/L (a cutoff considered by many (2) to indicate a low level of vitamin D). Almost all of the participants had a baseline 25OHD that was less than 75 nmol/L, which is considered an adequate level. Only four trials (6%) studied people with vitamin D deficiency (25OHD <25 nmol/L), in whom vitamin D supplementation may produce different results. In addition, there can be individual differences in how the body’s level of vitamin D responds to the administration of a fixed dose of Vitamin D. Most studies used 1,000 IU per day or less, and so the 25OHD levels after treatment (used as the intervention) may not have been high enough to make a difference in the health outcomes studied (fractures and falls).

Second, the finding that vitamin D alone (without calcium) may not prevent fractures, falls or improve bone mineral density is consistent with other published reviews. However, a review of studies of calcium and vitamin D for people living in long-term care showed benefit (3) but the current meta-analysis by Bolland and colleagues included only 20 trials (25%) that compared vitamin D and calcium to calcium alone. They also did not include studies that compared vitamin D and calcium with no treatment.

Third, although the major strength of the current review lies in the large number of studies included in the analysis, it is important to recognize there are potential limitations. For example, there were differences in the participants enrolled between studies, the study designs, and the results of the studies in the meta-analysis. Importantly, this review did not specifically address the vitamin D requirements of people with osteoporosis, those with risk factors for low trauma fractures, or those with risk factors for vitamin D deficiency. Although this systematic review suggests that routine vitamin D supplementation, in particular, high dose vitamin D, may not be necessary for healthy individuals in the general population, these findings cannot be applied to people with osteoporosis, or to those with risk factors for fractures or vitamin D deficiency.

Fourth, it must be highlighted that falls have many causes. Even specific fall prevention exercise programs are not always effective, and the relative benefit of any intervention on falls is individual.

It is important to remember that vitamin D is needed to optimize calcium absorption from the gut, and plays an important role in calcium balance and bone mineralization. Inadequate vitamin D can result in poor bone mineralization, as well as bone loss due to a rise in parathyroid hormone levels.

Osteoporosis Canada recommends that individuals with osteoporosis or with risk factors for fractures receive adequate vitamin D, as recommended at 800-2,000 IU per day (4); however, vitamin D dosing may require adjustment in order to achieve the adequate 25OHD level needed for optimal calcium homeostasis. Further studies are needed to clarify the optimal 25OHD level for those with osteoporosis or with risk factors for fracture. High dose vitamin D supplementation should be avoided due to potential harms (5). There are large randomized trials currently ongoing to help answer questions about effects of vitamin D supplementation on other aspects of health (6).

Appropriate osteoporosis medication may be required for those at high fracture risk. It is important to note that clinical trials showing the effectiveness of osteoporosis medications all included vitamin D and calcium as part of the treatment regimen.

References:

1. Bolland et al. Lancet Diabetes Endocrinol Oct 2018

2. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. Michael F. Holick et al. The Journal of Clinical Endocrinology & Metabolism, 2011 96 (7): 1911-1930.

3. Papaioannou et al. CMAJ 2015 187: 1-11.

4. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada by David A. Hanley MD et al CMAJ 2010

5. Smith et al. 2017 J Steroid Biochem Mol Biol173:317-22

6. Pradhan AD, Manson JE Update on the Vitamin D and OmegA-3 trial (VITAL). Study J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):252-6.

Updated: November 25 2024

Update Authors: Dr. Adrian Lau, Dr. Rowena Ridout, Dr. Laetitia Michou, Dr. Claudia Gagnon, Dr. Vithika Sivabalasundaram, Dr. Emma Billington, Dr. Zahra Bardai

A study published by Drieling and colleagues 2017 (1) described the results of a cohort study of 5120 older women with an average age of 80 years and at high fracture risk. This observational study from the Women’s Health Initiative included 5120 women who had been using oral bisphosphonates for at least 2 years and had a 5-year hip fracture risk of 1.5% or higher. Women who had been on parathyroid analogues, calcitonin or aromatase inhibitors were excluded. The average follow-up data was available for 4 years.

10-13 years of oral bisphosphonate use was associated with a higher risk of any clinical fracture than 2 years of use (HR =1.29, 95% CI 1.07-1.57).

There was no association between intermediate use and fracture risk. There are a number of limitations to this observational data including the fact that this study did not include a group without bisphosphonate use.  Also, compliance was not evaluated.

Oral bisphosphonates have been shown to significantly reduce the risk of vertebral and nonvertebral fracture in randomized controlled trials. Among patients with osteoporosis (defined as T-score < -2.5, or prior fragility fracture), bisphosphonate therapy provides a risk reduction of about 50% for vertebral, 30% for hip, and 20% for nonvertebral fractures after 3 years of treatment. The extension studies of these fracture trials unfortunately were not powered to evaluate impact on fracture risk.  Currently we do not have data consistently demonstrating reductions in nonvertebral fracture risk with long-term bisphosphonate use.

It appears that the optimal period of use for oral or IV bisphosphonates is 3-6 yrs with published randomized controlled trial data confirming reductions in fracture risk for vertebral, nonvertebral and hip fracture with use for this time period.

Osteoporosis Canada advises that all patients should have their fracture risk and treatment strategy reviewed by their physicians after 3-6 years of bisphosphonate use, as long-term use may not have the same risk-benefit ratio as seen with shorter term use.

1. Drieling RL, LaCroix AZ, Beresford SAA, Boudreau DM, Kooperberg C, Chlebowski RT, Ko MG, Heckbert SR. Long-Term Oral Bisphosphonate Therapy and Fractures in Older Women: The Women’s Health Initiative. J Am Geriatr Soc. 2017 Sep;65(9):1924-1931. doi: 10.1111/jgs.14911. Epub 2017 May 29. PMID: 28555811; PMCID: PMC5603349.

Bisphosphonate therapy – long term use

Recently a study published by Drieling et al in JAGS 2017 described the results of a cohort study of 5120 older women with an average age of 80 yrs and at high fracture risk . This observational study from the Womens Health Initiative included 5120 women who had been using oral BP for at least 2 years and had a FRAX score of 1.5% or higher for 5 yrs. Women who had been on PTH , calcitonin or aromatase inhibitors were excluded. The average follow up data was available for 4 yrs.

10-13 yrs of oral bisphosphonate use was associated with higher risk of any clinical fracture then 2 yrs of use HR =1.29 , 95% CI 1.07-1.57.

There was no association between intermediate use and fracture risk. There are a number of limitations to this observational data including the fact that this study did not include a group without bisphosphonate use also compliance was not evaluated.

Oral BPs have been shown to significantly reduce the risk of vertebral and non vertebral fracture in randomized controlled trials. The extension studies of these fracture trials unfortunately were not powered to evaluate impact on fracture risk and currently we do not have long term data consistently demonstrating reductions in non vertebral fracture risk with long term BP use.

It appears that the optimal period of use for oral or IV bisphosphonates is 3-5 yrs with published randomized controlled trial data confirming reductions in fracture risk for vertebral , non vertebral and hip fracture with use for this time period. After the first 5 years of bisphosphonate use the fracture risk should be re-evaluated and bisphosphonate therapy should also be re-evaluated.

Osteoporosis Canada advises that all patients should have their treatment strategy reviewed by their physicians particularly after 5 years of use as long term use of bisphosphonates may not have the same risk benefit ratio as seen with short term use of up to 5 yrs.

On September 29, 2015, two research articles were published online in the British Medical Journal (BMJ) concerning the effect of calcium intake on bone mineral density (BMD) and fracture reduction. These have been widely reported in the media.

The full text of the Osteoporosis Canada response can be found on the website at http://www.osteoporosis.ca/calcium-intake-and-effect-on-bone-health-and-fracture-risk-reduction/

The following is a summary of the OC response.

The first study published in the BMJ summarizes the results of 59 earlier studies to evaluate the effects of calcium intake on BMD in people over the age of 50. According to this study, both extra dietary calcium intake and the use of calcium supplements were associated with small increases in BMD. A small reduction in fractures was observed with calcium supplementation. The authors concluded that calcium intake from dietary sources and supplements increase BMD similarly, but that this is unlikely to reduce fractures.

The second study explored whether calcium could reduce fractures. This study did not show a significant reduction in fracture risk in the large randomized trials with calcium supplementation.

The two studies significantly differed in both the numbers of people evaluated and in the quality of the assessments. They also differed in how fractures were identified. As a result, in order to better determine the effects of calcium supplementation on bone health, additional research is needed using well-designed, large, controlled studies.

Every cell in our body requires calcium in order to function normally. Inadequate calcium intake results in the release of calcium from our bones in order to meet our daily requirements. Because of this, Osteoporosis Canada continues to recommend 1000-1200 mg of calcium daily, preferably from dietary sources, and to use supplements only if this is not possible (in the form of calcium carbonate or calcium citrate).

Click here for more detailed information on Osteoporosis Canada’s nutritional recommendations

However, in individuals with osteoporosis or high fracture risk, there is no research evidence supporting the use of calcium supplements alone as a treatment to prevent fractures. Such individuals may require medication in addition to adequate calcium intake and vitamin D supplementation in order to reduce their fracture risk.

Click here for more information on drug treatments for osteoporosis