A New Risk Factor for People with Osteoporosis - Homocysteine

Summarized by Robert W. Griffith, MD
July 2, 2004

Introduction

In older people, osteoporosis is a major risk factor for fractures, and there are numerous risk factors for osteoporosis: lack of dietary calcium and vitamin D, physical inactivity, smoking, excess alcohol, and the menopause. Now there's news of another potential risk factor - raised blood homocysteine levels.

High homocysteine levels are known to be associated with an increased risk of cardiovascular disease, such as heart attack and stroke. But two analyses reported in the New England Journal of Medicine suggest that the risk of an osteoporotic fracture may be just as great.^{1 , 2}

What the two analyses showed

The first was an analysis of data from two large studies being conducted in the Netherlands - the Rotterdam Study and the Longitudinal Aging Study Amsterdam.¹ There were 2406 participants, aged 55 or older, who were followed for periods of 2½ to 8 years. They were allocated to four equally-sized groups, or quartiles, based on their blood homocysteine levels. The number of fractures involving bones other than the spine was doubled in the highest homocysteine quartile subjects compared with those in the lower three quartiles. This was after adjustment for possible confusing factors such as age, sex, dietary supplements, bone mineral density, BMI, smoking, recent falls, diabetes, and dementia.

The second analysis was done on people in the renowned Framingham Study.² There were 1999 subjects aged 59 to 91, who were followed for 16 to 19 years. Homocysteine level quartiles were formed for both sexes in the same way as in the first analysis. In this study, the frequency of fracture was quadrupled in men and doubled in women in the highest quartiles, compared with the three lower quartiles for each sex.

Is Homocysteine a "Culprit" or a "Bystander"?

There's a rare inherited disease, homocystinuria, in which the blood homocysteine levels are high and the urine excretes a lot of homocysteine; in this condition, there's also generalized osteoporosis. This makes a strong argument that homocysteine itself can produce osteoporosis, even though the intermediate steps haven't been shown in the research lab.

On the other hand, increased homocysteine levels rarely occur in isolation. They are often accompanied by decreased folic acid, vitamin B12 and pyridoxine levels; and there's a clear link between low folic acid and B12 levels and an increased rate of bone loss in postmenopausal women. Maybe one of these substances is the "culprit" while homocysteine is merely a "bystander". In favor of the "bystander" role is the finding that homocysteine levels increase during menopause, and can be reduced by estrogen administration (but so can osteoporosis!).

What all this means

Whatever the actual role of homocysteine, the elevations seen in the highest quartiles in these analyses raised the fracture risk to the same extent as that seen in subjects with low bone mineral density, dementia, or recent falls. This makes the blood homocysteine level a potentially useful "marker" for detecting people at risk of an osteoporosis-related fracture. (Normal homocysteine levels are between 6 and 12 micromoles per liter.)

As elevated homocysteine levels are associated with a number of other conditions (mostly cardiovascular), it makes sense to see that your diet contains enough folic acid to ensure your homocysteine is "within normal limits". This means eating plenty of the right foods (fruits and green leafy vegetables - see second link below).

Source

• Homocysteine and osteoporotic fractures - culprit or bystander? LG. Raisz, Editorial. N Engl J Med, 2004, vol. 350, pp. 2089--2090

Footnotes
1. Homocysteine levels and the risk of osteoporotic fracture. JBJ. van Meurs, RAM. Dhonukshe-Rutten, SFP. Pluijm,  et al., N Engl J Med, 2004, vol. 350, pp. 2033--2041
2. Homocysteine as a predictive factor for hip fracture in older persons. RR. McLean, PF. Jacques, J. Selhub,  et al., N Engl J Med, 2004, vol. 350, pp. 2042--2049

Related Links
AHA: Homocysteine, Folic Acid and Cardiovascular Disease
Folate Part of a Heart Healthy Diet

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