In the Journals

Fracture risk genetically correlated to BMD

Bone mineral density is an important potentially modifiable genetic predictor of osteoporotic fracture, whereas genetically influenced levels of vitamin D and calcium may not be, according to findings from a genome-wide association and Mendelian randomization study.

Fernando Rivadeneira

“The causes of multifactorial common diseases, such as osteoporotic fractures, include genetic and environmental influences, as well as their interactions. ... Clinically useful risk factors for the prediction of osteoporotic fracture risk need not be necessarily causal and have been implemented by well-validated risk score algorithms,” Fernando Rivadeneira, MD, PhD, a genetic epidemiologist in the department of internal medicine at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues wrote in the study background. “The extent to which modification of predictive clinical risk factors reduces fracture risk is not generally known. A better understanding of causal mechanisms will enable prevention strategies, direct the launch of proper clinical trials, and provide targets for effective lifestyle and pharmacological interventions.”

Researchers analyzed data from 23 cohorts of adults of predominantly European descent from the Genetic Factors for Osteoporosis consortium and two large genome-wide association studies, including 37,857 cases of fracture and 227,116 controls (age range, 18-106 years; 69% women), to identify genetic markers associated with fracture. These single nucleotide polymorphisms were replicated in an additional cohort from the personal genetics company 23andMe (147,200 cases and 150,085 controls). Summary results from genome-wide association studies were used to perform two-sample Mendelian randomization, evaluating 15 potential risk factors for osteoporotic bone fracture: BMD, rheumatoid arthritis, type 1 diabetes, age at menopause, inflammatory bowel disease, thyroid-stimulating hormone, homocysteine levels, grip strength, age at puberty, fasting glucose levels, coronary heart disease, type 2 diabetes, vitamin D levels and calcium intake.

Researchers found that the genetic correlation between BMD, both at the femoral neck (–0.59; P = 2x10-24) and lumbar spine (–0.53; P = 1x10-20), and osteoporotic fracture was the most significant of the examined risk factors. Grip strength (–0.1; P = .07) and homocysteine levels (0.22; P = .004) were factors that exhibited some correlation but did not reach statistical significance. All other factors, including vitamin D levels and calcium intake, did not meet the criteria required for correlation.

“Using Mendelian randomization analyses, we demonstrated that genetically decreased bone mineral density (and, to a lesser extent, hand grip strength) was the only clinical risk factor among those tested, with evidence for an effect on fracture risk,” the researchers wrote. “By contrast, despite high statistical power, none of the other tested and well-accepted risk factors (eg, rheumatoid arthritis and other causes of secondary osteoporosis) or any of the other clinically relevant risk factors (vitamin D levels, dairy food-derived calcium intake, fasting glucose, type 2 diabetes, and coronary heart disease) had evidence of a major causal effect on fracture risk. Furthermore, all identified genetic determinants of fracture also influenced bone mineral density.”

The researchers noted that the absence of a connection found with certain factors, especially vitamin D levels, did not constitute a complete dismissal of their effect on fracture risk.

“It is unclear whether modestly low levels of vitamin D, rather than profoundly low values,

are causally associated with a higher risk of fracture,” the researchers wrote. “Although a threshold effect is likely to be present, where profoundly lowered vitamin D levels do increase risk of fracture, our Mendelian randomization results strongly suggest that increasing levels of vitamin D in the (non-deficient) general population is unlikely to decrease risk of fracture.”

The researchers also stated that their findings do not necessarily correlate to all real-world conditions and that further study with greater ethnic diversity is needed. Other potential fracture risk factors, such as BMI, should be investigated.

“Our findings suggest that low bone mineral density (not only after reaching the osteoporotic range) constitutes a risk factor that captures a substantial and causal part of the influences that increase risk for all types of fracture,” the researchers wrote. “Therefore, interventions targeting an increase in bone mineral density (presuming this is associated with improvements in bone structure or quality) are likely to have pivotal roles in reducing fracture risk.” – by Phil Neuffer

Disclosures: Rivadeneira reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Bone mineral density is an important potentially modifiable genetic predictor of osteoporotic fracture, whereas genetically influenced levels of vitamin D and calcium may not be, according to findings from a genome-wide association and Mendelian randomization study.

Fernando Rivadeneira

“The causes of multifactorial common diseases, such as osteoporotic fractures, include genetic and environmental influences, as well as their interactions. ... Clinically useful risk factors for the prediction of osteoporotic fracture risk need not be necessarily causal and have been implemented by well-validated risk score algorithms,” Fernando Rivadeneira, MD, PhD, a genetic epidemiologist in the department of internal medicine at Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues wrote in the study background. “The extent to which modification of predictive clinical risk factors reduces fracture risk is not generally known. A better understanding of causal mechanisms will enable prevention strategies, direct the launch of proper clinical trials, and provide targets for effective lifestyle and pharmacological interventions.”

Researchers analyzed data from 23 cohorts of adults of predominantly European descent from the Genetic Factors for Osteoporosis consortium and two large genome-wide association studies, including 37,857 cases of fracture and 227,116 controls (age range, 18-106 years; 69% women), to identify genetic markers associated with fracture. These single nucleotide polymorphisms were replicated in an additional cohort from the personal genetics company 23andMe (147,200 cases and 150,085 controls). Summary results from genome-wide association studies were used to perform two-sample Mendelian randomization, evaluating 15 potential risk factors for osteoporotic bone fracture: BMD, rheumatoid arthritis, type 1 diabetes, age at menopause, inflammatory bowel disease, thyroid-stimulating hormone, homocysteine levels, grip strength, age at puberty, fasting glucose levels, coronary heart disease, type 2 diabetes, vitamin D levels and calcium intake.

Researchers found that the genetic correlation between BMD, both at the femoral neck (–0.59; P = 2x10-24) and lumbar spine (–0.53; P = 1x10-20), and osteoporotic fracture was the most significant of the examined risk factors. Grip strength (–0.1; P = .07) and homocysteine levels (0.22; P = .004) were factors that exhibited some correlation but did not reach statistical significance. All other factors, including vitamin D levels and calcium intake, did not meet the criteria required for correlation.

“Using Mendelian randomization analyses, we demonstrated that genetically decreased bone mineral density (and, to a lesser extent, hand grip strength) was the only clinical risk factor among those tested, with evidence for an effect on fracture risk,” the researchers wrote. “By contrast, despite high statistical power, none of the other tested and well-accepted risk factors (eg, rheumatoid arthritis and other causes of secondary osteoporosis) or any of the other clinically relevant risk factors (vitamin D levels, dairy food-derived calcium intake, fasting glucose, type 2 diabetes, and coronary heart disease) had evidence of a major causal effect on fracture risk. Furthermore, all identified genetic determinants of fracture also influenced bone mineral density.”

PAGE BREAK

The researchers noted that the absence of a connection found with certain factors, especially vitamin D levels, did not constitute a complete dismissal of their effect on fracture risk.

“It is unclear whether modestly low levels of vitamin D, rather than profoundly low values,

are causally associated with a higher risk of fracture,” the researchers wrote. “Although a threshold effect is likely to be present, where profoundly lowered vitamin D levels do increase risk of fracture, our Mendelian randomization results strongly suggest that increasing levels of vitamin D in the (non-deficient) general population is unlikely to decrease risk of fracture.”

The researchers also stated that their findings do not necessarily correlate to all real-world conditions and that further study with greater ethnic diversity is needed. Other potential fracture risk factors, such as BMI, should be investigated.

“Our findings suggest that low bone mineral density (not only after reaching the osteoporotic range) constitutes a risk factor that captures a substantial and causal part of the influences that increase risk for all types of fracture,” the researchers wrote. “Therefore, interventions targeting an increase in bone mineral density (presuming this is associated with improvements in bone structure or quality) are likely to have pivotal roles in reducing fracture risk.” – by Phil Neuffer

Disclosures: Rivadeneira reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.