Can homocysteine levels predict risk of osteoporosis?

[Guest guest]

Rheumawire

May 12, 2004

Can homocysteine levels predict risk of osteoporosis?

Boston, MA - Two new observational studies suggest that increased

homocysteine levels are a risk factor for osteoporosis in older men and

women The studies appear in this week's New England Journal of Medicine

[1,2]

And although it remains to be determined whether this is cause or

effect, " homocysteine can now be added to the growing list of risk

factors for fractures, " says an accompanying editorial [3]. Its use

might increase the predictive power of an assessment based on multiple

risk factors, something that is sorely needed, it adds.

" If homocysteine concentration truly is a causal mechanism for the risk

of fracture, the public-health implications could be substantial,

because total homocysteine concentrations can be easily modified by

dietary intake of folic acid and vitamins B6 and B12, " say Dr R

McLean (Hebrew Rehabilitation Center for the Aged, Boston, MA) and

colleagues, authors of 1 of the studies. McLean presented these findings

for the first time at the American Society of Bone and Mineral Research

meeting in Minneapolis last year, reported then by rheumawire.

But he warned rheumawire: " This is pretty far from prime time. We saw

the association but weren't able to establish a causal mechanism. "

In the other study, the effect of high homocysteine levels on the risk

of fracture was similar in magnitude to that of low bone-mineral

density, cognitive impairment, and recent falls, report Dr Joyce van

Meurs (Erasmus Medical Center, Rotterdam, the Netherlands) et al.

Homocysteine is an amino acid intermediate formed during the metabolism

of methionine, and an elevated level is recognized as a major risk

factor for atherosclerotic and thromboembolic disease, as well as for

cognitive impairment, including that seen in Alzheimer's disease. People

with homocystinuriaa rare autosomal recessive disease characterized by

high homocysteine levelssuffer from the early onset of generalized

osteoporosis, and it is this observation that prompted both groups to

look at the association between homocysteine and fractures.

McLean and colleagues, using data from almost 2000 participants in the

Framingham Study, found that the risk of hip fracture was increased by a

factor of nearly 4 in men (hazard ratio 3.84) and 2 in women (HR 1.92)

for the highest quartile of plasma homocysteine levels compared with the

lowest quartile.

McLean et al explain that the apparent differences according to sex

found in their study can be explained by the lower background incidence

of hip fracture in men. The true effect of the homocysteine

concentration on the risk of hip fractures " is most likely very similar

in men and women. " But in women, only those in the highest quartile were

at increased risk for hip fracture, " which suggests a possible threshold

effect, " they note.

Van Meurs et al looked at 2406 subjects aged 55 years or oldertwo

cohorts from the Rotterdam study and a single cohort from the

Longitudinal Aging Study Amsterdam (LASA). They showed that subjects in

the highest quartile of homocysteine levels had a risk of nonvertebral

fractures (hip and wrist) that was twice the risk of those in the other

3 quartiles.

" The magnitude of this effect is similar to that previously observed for

the increase in the risk of cardiovascular disease and dementia,

according to homocysteine level, " they state.

In the accompanying editorial, Dr Lawrence G Raisz (University of

Connecticut Center for Osteoporosis, Farmington) observes, " The degree

of association between homocysteine levels and the risk of osteoporotic

fractures as shown in these 2 studies is of similar magnitude. " Neither

study assessed the incidence of vertebral fractures, he notes.

Raisz goes on to ponder the question of whether or not homocysteine is a

cause of fractures. Both groups mention the link between homocystinuria

and osteoporosis and say that this has been attributed to an inhibition

of collagen cross-linking by high homocysteine levels, he notes. " But in

vivo evidence of the link between homocysteine and generalized

osteoporosis is limited, " he points out, adding that additional

biochemical data are needed to determine whether homocysteine truly is a

culprit.

McLean concurs. He told rheumawire, " We need more biochemistry studies

to see whether there is a direct effect of homocysteine on bone. "

Equally, says Raisz, homocysteine could be an innocent bystander. For

example, it is possible that high homocysteine levels are simply a

reflection of poor nutrition, he suggests. However, the data from 1

cohort of the Netherlands study were adjusted for nutritional intake,

including calcium, folate, and vitamins B6, B12, and D, but the risk

estimates were not altered.

Another explanation, in women at least, could be that high homocysteine

is simply a reflection of estrogen deficiency, because postmenopausal

women in the lowest quartile of estrogen concentrations have a risk of

fracture that is twice that of women in the highest quartilesimilar to

the increase in risk reported with high homocysteine levels. " It is

important to determine whether there is an association between these low

estrogen levels and high homocysteine levels, " Raisz says.

The authors of both papers and the editorialist agree that the

association between elevated homocysteine levels and the risk of

fracture needs to be confirmed in large population studies.

Fracture data must be collected from studies looking at the effects of

altering homocysteine levels in cardiovascular disease, Raisz says,

because it would be unethical to determine whether reducing homocysteine

levels with nutritional supplements reduces the incidence of fractures

in those with osteoporosis, " since effective therapy is available for

those patients. "

Also, measurements of homocysteine could be added to ongoing

epidemiologic studies of risk factors in osteoporosis, but these need to

be combined with better nutritional analysis, the editorialist says.

In the meantime, it remains to be seen whether fortification of grain

products with folic acid, as mandated by the FDA, will affect future

rates of hip fracture in the US, McLean et al conclude.

Nainggolan

Sources

1. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive

factor for hip fracture in older persons. N Eng J Med 2004;

350:2042-2049.

2. van Meurs JBJ, Dhonukshe-Rutten RAM, Pluijm SMF, et al. Homocysteine

levels and the risk of osteoporotic fracture. N Eng J Med 2004;

350:2033-2041.

3. Raisz LG. Homocysteine and osteoporotic fractures--culprit or

bystander? N Eng J Med 2004; 350:2089-2090.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org