Homocysteine Levels May Be Related to Osteoporosis

Laurie Barclay, MD

May 12, 2004

May 12, 2004 -- Homocysteine levels are associated with osteoporotic hip fracture, according to the results of two studies published in the May 13 issue of the New England Journal of Medicine. The editorialist discusses the issue of causality but basically agrees that homocysteine can be added to the list of risk factors for osteoporosis.

"Very high plasma homocysteine levels are characteristic of homocystinuria, a rare autosomal recessive disease accompanied by the early onset of generalized osteoporosis," write Joyce B. J. van Meurs, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands. "Although a previous study suggested the possible involvement of increased plasma homocysteine levels in age-dependent bone loss, the role of moderately elevated plasma homocysteine levels in diseases of the skeletal system -- in particular, osteoporotic fracture -- is unknown."

The investigators studied the association between circulating homocysteine levels and the risk of incident osteoporotic fracture in 2,406 subjects, aged 55 years or older, enrolled in two separate prospective, population-based studies. There were 562 subjects in cohort 1 of the Rotterdam Study, 553 subjects in an independent cohort (cohort 2) of the Rotterdam Study, and 1,291 subjects in the Longitudinal Aging Study Amsterdam. The mean follow-up periods were 8.1 years, 5.7 years, and 2.7 years, respectively.

Osteoporotic fractures occurred in 191 subjects during 11,253 person-years of follow-up. After adjustment for age, sex, body mass index, smoking, recent falls, dementia, diabetes mellitus, peripheral arterial disease, nutritional deficiency, and other risk factors for fracture, the overall multivariable-adjusted relative risk [RR] of fracture was 1.4 (95% confidence interval [CI], 1.2 - 1.6) for each increase of 1 SD in the natural-log-transformed homocysteine level.

Fracture risk was similar in both sexes and in all three cohorts. Patients in the highest age-specific quartile for homocysteine level had a 90% increase in fracture risk (RR, 1.9; 95% CI, 1.4 - 2.6). Based on multivariate Cox proportional-hazards regression models, these associations were independent of bone mineral density and other potential risk factors for fracture.

Study limitations include those inherent in use of dietary questionnaires, possible confounding by nutritional deficiency, and differences in the techniques used to assess homocysteine levels and in the age and sex distribution in the three study cohorts.

"An increased homocysteine level appears to be a strong and independent risk factor for osteoporotic fractures in older men and women," the authors write, while recommending that this risk be confirmed in other large population studies. "Proof of a causal relationship between increased homocysteine levels and bone disease could be established by intervention studies aimed at lowering the serum homocysteine level. Whereas randomized, controlled trials have shown that folic acid-based vitamin supplements can effectively reduce homocysteine levels and reduce the rate of coronary restenosis, additional studies are needed to assess whether the use of such therapy will reduce the risk of fracture."

The Nederlandse Organisatie voor Wetenschappelijk Onderzoek, the Praeventiefonds of The Hague, and the Dutch Dairy Association supported this research. The Netherlands Ministry of Health, Welfare, and Sports supported the Rotterdam Study and the Longitudinal Aging Study Amsterdam. Two of the authors report various financial relationships with Wyeth, Lilly, Merck, Servier, Aventis, and/or Organon.

The second study looked at the association between total homocysteine concentration and the risk of hip fracture in men and women enrolled in the Framingham Study.

"The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture," write Robert R. McLean, MPH, from the Hebrew Rehabilitation Center for Aged Research and Training Institute in Boston, Massachusetts, and colleagues.

Between 1979 and 1982, blood samples to measure plasma total homocysteine were obtained from 825 men and 1,174 women, ranging in age from 59 to 91 years. Mean plasma total homocysteine concentration was 13.4 ± 9.1 µmol/L in men and 12.1 ± 5.3 µmol/L in women. Follow-up continued through June of 1998, with median follow-up periods of 12.3 years for men and 15.0 years for women.

During follow-up, there were 41 hip fractures in the men and 146 hip fractures in the women. Compared with men and women in the lowest quartile for total homocysteine, those in the highest quartile had nearly quadruple the risk of hip fracture for men and nearly double for women, based on Cox proportional-hazards regression. From the lowest to the highest quartile, the age-adjusted incidence rates for hip fracture per 1,000 person-years were 1.96 (95% CI, 0.52 - 3.41), 3.24 (0.97 - 5.52), 4.43 (1.80 - 7.07), and 8.14 (4.20 - 12.08) for men, and 9.42 (5.72 - 13.12), 7.01 (4.29 - 9.72), 9.58 (6.42 - 12.74), and 16.57 (11.84 - 21.30) for women.

Study limitations include white population precluding generalizability to other racial and ethnic groups, use of nonfasting blood samples, use of a single measurement performed during the 20-year follow-up period, which may have underestimated the relative risk of hip fracture based on homocysteine concentration, and lack of dietary information at baseline causing potential confounding due to dietary factors. Because no data on bone mineral density were available at baseline, the investigators could not assess whether the effect of homocysteine on hip fracture may be mediated through bone mineral density.

"These findings suggest that the homocysteine concentration, which is easily modifiable by means of dietary intervention, is an important risk factor for hip fracture in older persons," the authors write. "Further population-based research is needed to examine the role of homocysteine in osteoporosis and osteoporotic fracture and to determine whether nationwide folic acid fortification of food will help to reduce rates of hip fracture in the United States."

The National Institutes of Health, the National Heart, Lung, and Blood Institute, and the Department of Agriculture Research Service supported this study. One author reports financial arrangements with AgeWave, Syngenta, and the Vitamin Nutrition Information Service. Another author, who holds a patent on methods of vitamin composition in the treatment of osteoarthritis, reports financial arrangements with Eprova, Pamlab, Cooper Clinic, and VitaMed.

In an accompanying editorial, Lawrence G. Raisz, MD, from the University of Connecticut Health Center in Farmington, discusses whether there is a causal relationship between homocysteine levels and osteoporosis.

"Whether it is a culprit or a bystander, homocysteine can now be added to the growing list of risk factors for fractures," Dr. Raisz writes. "Its use might increase the predictive power of an assessment based not just on bone mineral density, but on multiple risk factors. Such an assessment is sorely needed to provide realistic individualized estimates of the risk of fracture that can guide physicians and patients in planning prevention and treatment."

N Engl J Med. 2004;350:2033-2041, 2042-2049, 2089-2090

Reviewed by Gary D. Vogin, MD

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