Calcium and Vitamin D for the Prevention of Fracture
JAMA Network: A Systematic Review and Meta-analysis
Osteoporosis is characterized by reduced bone mass and fragmentation of bone architecture, resulting in an increased risk of fracture. Approximately 1 in 2 women and 1 in 5 men aged 50 years or older will experience an osteoporotic fracture in their remaining lifetime. Hip fracture is the most serious type of osteoporotic fracture, with an approximate 30% risk of death in the year following hip fracture.
Vitamin D is essential for optimal musculoskeletal health because it promotes calcium absorption, mineralization of osteoid tissue formation in bone, and maintenance of muscle function. Low vitamin D status causes secondary hyperparathyroidism, bone loss, and muscle weakness.
Observational studies have reported that lower blood concentrations of 25-hydroxyvitamin D (25[OH]D) are associated with higher risks of falls and fractures.
Combined supplementation with 800 IU of vitamin D per day and 1200 mg of calcium per day has been recommended for prevention of fractures in older adults living in institutions and in those with low vitamin D status.
However, previous randomized clinical trials (RCTs) and meta-analyses of vitamin D alone or in combination with calcium for the prevention of fracture in either community-dwelling or general population settings reported conflicting results, with some reporting protective effects against fractures and others demonstrating no beneficial effects.
To summarize the available evidence and guide clinical practice, authors conducted parallel meta-analyses.
Key Points
Question What is the available evidence for the efficacy of vitamin D with or without calcium supplementation for reducing the risk of fracture?
Findings This systematic review and meta-analysis of randomized clinical trials of vitamin D alone (11 randomized clinical trials with 34 243 participants) showed no significant association with risk of any fracture or of hip fracture.
In contrast, daily supplementation with both Calcium and Vitamin D (6 randomized clinical trials with 49 282 participants) was associated with a 16% reduced risk of hip fracture.
Meaning In this study, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily treatment with both Calcium and Vitamin D was a more promising strategy.
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Importance Vitamin D and calcium supplements are recommended for the prevention of fracture, but previous randomized clinical trials (RCTs) have reported conflicting results, with uncertainty about optimal doses and regimens for supplementation and their overall effectiveness.
Objective To assess the risks of fracture associated with differences in concentrations of 25-hydroxyvitamin D (25[OH]D) in observational studies and the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs.
Data Sources PubMed, EMBASE, Cochrane Library, and other RCT databases were searched from database inception until December 31, 2018. Searches were performed between July 2018 and December 2018.
Study Selection Observational studies involving at least 200 fracture cases and RCTs enrolling at least 500 participants and reporting at least 10 incident fractures were included. Randomized clinical trials compared vitamin D or vitamin D and calcium with control.
Data Extraction and Synthesis Two researchers independently extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and assessed possible bias. Rate ratios (RRs) were estimated using fixed-effects meta-analysis. Data extraction and synthesis took place between July 2018 and June 2019.
Main Outcomes and Measures Any fracture and hip fracture.
Results In a meta-analysis of 11 observational studies (39 141 participants, 6278 fractures, 2367 hip fractures), each increase of 10.0 ng/mL (ie, 25 nmol/L) in 25 (OH)D concentration was associated with an adjusted RR for any fracture of 0.93 and an adjusted RR for hip fracture of 0.80. A meta-analysis of 11 RCTs (34 243 participants, 2843 fractures, 740 hip fractures) of vitamin D supplementation alone (daily or intermittent dose of 400-30 000 IU, yielding a median difference in 25[OH]D concentration of 8.4 ng/mL) did not find a reduced risk of any fracture or hip fracture, but these trials were constrained by infrequent intermittent dosing, low daily doses of vitamin D, or an inadequate number of participants. In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with vitamin D (daily doses of 400-800 IU, yielding a median difference in 25[OH]D concentration of 9.2 ng/mL) and calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture and a 16% reduced risk of hip fracture.
Conclusions and Relevance In this systematic review and meta-analysis, neither intermittent nor daily dosing with standard doses of vitamin D alone was associated with reduced risk of fracture, but daily supplementation with both vitamin D and calcium was a more promising strategy.
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