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. 2000 Jun 17;320(7250):1669.

Genetic factors and osteoporotic fractures in elderly people

Twin data support genetic contribution to risk of fracture

Alex J MacGregor 1,2, Harold Snieder 1,2, Tim D Spector 1,2
PMCID: PMC1127438  PMID: 10905839

Editor—Kannus et al suggest from prospective data collected on Finnish twins that genetic factors are of only minor importance in explaining the population occurrence of osteoporotic fracture, particularly in women.1

The evidence given to support this is the relatively small excess in concordance in monozygotic twins compared with dizygotic twins. But it is well recognised that twin concordances may be misleading unless the underlying prevalence of a disease is taken into account.2 For example, a small absolute difference in monozygotic compared with dizygotic concordance is more suggestive of a genetic effect for a trait that is relatively rare (such as fracture) than for one that is common. The data thus warrant closer scrutiny.

We have estimated the relative contribution of genetic, shared environmental, and unique environmental components to the variation in susceptibility to fracture in these twins from the data provided. The analysis was conducted using a variance components approach with the statistical software Mx.3 The method assumes that risk of fracture is determined by a continuous underlying liability and is a plausible assumption for this trait.4

As expected, the results show significant evidence of familial resemblance in the risk of fracture in both male and female twins. In female twins, despite the nationwide sampling frame, there is insufficient statistical power in this study to distinguish between models containing components in which this clustering is attributed to genetic factors alone, the shared family environment of the twins, or the combination of the two. In a model in which the only contribution is from genetic and unique environmental factors, genetic factors account for 36% of the variance in the liability to fracture at any body site.

In male twins the familial resemblance is explained by a significant contribution from genetic factors but not by the shared family environment, with genetic factors accounting for 35% of the variation in liability to fracture. A greater genetic contribution is also suggested at the spine in table A in Kannus et al's study (bmj.com/cgi/content/full/319/7221/1334/DC1), although inference is limited by the small numbers of concordant pairs and the lack of data on differences between the sexes in rate of fracture. In contrast to the conclusion reached by the authors, these data show that genetic factors contribute to a third of the liability to osteoporotic fracture in men and are entirely compatible with the hypothesis that genetic factors contribute to a similar extent in women. The data suggest that there may be differences in the nature of the genetic risk in men and women and at different body sites that merit further study.

References

  • 1.Kannus P, Palvanen M, Kaprio J, Parkkari J, Koskenvuo M. Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins. BMJ. 1999;319:1334–1337. doi: 10.1136/bmj.319.7221.1334. . (20 November.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Smith C. Concordance in twins: methods and interpretation. Am J Hum Genet. 1974;26:454–466. [PMC free article] [PubMed] [Google Scholar]
  • 3.Neale MC. Mx: statistical modeling. 4th ed. Richmond, VA: Department of Psychiatry (Box 126 MCV, Richmond, VA 23298, USA); 1997. [Google Scholar]
  • 4.Falconer DS. Introduction to quantitative genetics. Harlow: Longman Scientific and Technical; 1989. [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1669.

Study supports possibility of differences in development of osteoporotic fractures between sexes

Andrea Nemetz 1,2, Amado Salvador Pena 1,2

Editor—Kannus et al report their large, long term prospective study analysing the genetic predisposition of osteoporotic fractures in elderly Finnish twins.1-1 It is important to note that whereas the concordance rate for fractures was indeed not strikingly different between monozygotic and dizygotic twin pairs in women, there was a fourfold difference in men.

In their electronic response to the article [published here in the paper journal, above] MacGregor et al have estimated the relative contribution of genetic components on the basis of the data provided; they found a strong role for genetic factors in men but not women.1-2 Previous studies have pointed to possible differences in the main regulatory factors in the development of low bone mineral density and osteoporotic fractures between the sexes. We suggest that the data presented by Kannus et al could be interpreted as further evidence supporting this hypothesis.

Bone density is suggested to be multifactorially regulated and polygenically determined. Underlying diseases such as inflammatory bowel disease and several drugs such as glucocorticosteroids can modulate and enhance the effect of genetic factors on the development of osteoporotic fractures. For example, our studies have shown that the allele 2 at the AvaI polymorphism in the interleukin-1 β gene—related to a higher production of the cytokine—is associated with a subgroup of patients (those with the non-fistulising form of Crohn's disease).1-3 Additionally, we have found a strong correlation between this polymorphism and bone mineral density in patients with inflammatory bowel diseases but not in healthy controls. We also found a difference between the two sexes: the association at the lumbar spine was present only in men.1-4

Bone loss at the cortical and trabecular bones seems to be influenced by several physiological and other elements such as the menopause or use of corticosteroids. Therefore, analysing data after screening for the often “silent” vertebral fractures could further modify Kannus et al's results concerning the importance of the genetic background.

Bone mineral density is a key predictor of osteoporotic fractures. To judge the weight of genetic influence it would be important to compare concordance rates in the groups with low and high Z score values. We suggest that studies in well defined subgroups of patients may help to define those conditions in which genetic background has a high prognostic value for the risk of osteoporotic fractures.

References

  • 1-1.Kannus P, Palvanen M, Kaprio J, Parkkari J, Koskenvuo M. Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins. BMJ. 1999;319:1334–1337. doi: 10.1136/bmj.319.7221.1334. . (20 November.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.MacGregor AJ, Snieder H, Spector TD. Twin data support a genetic contribution to fracture risk [electronic response to Kannus et al. Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins]. bmj.com 1999. www.bmj.com/cgi/eletters/319/7221/1334#EL1 (accessed 5 April). [DOI] [PMC free article] [PubMed]
  • 1-3.Nemetz A, Nosti-Escanilla MP, Molnár T, Köpe A, Kovács A, Fehér J, et al. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999;49:527–531. doi: 10.1007/s002510050530. [DOI] [PubMed] [Google Scholar]
  • 1-4.Nemetz A, Zágoni T, Tóth M, Kovács A, Nosti-Escanilla MP, García-González MA, et al. Interleukin-1 gene polymorphisms stimulate bone loss in inflammatory bowel diseases. Gut. 1999;45(suppl V):A15. [Google Scholar]
BMJ. 2000 Jun 17;320(7250):1669.

Authors' reply

Pekka Kannus 1,2,3,4,5, Jaakko Kaprio 1,2,3,4,5, Markku Koskenvuo 1,2,3,4,5, Mika Palvanen 1,2,3,4,5, Jari Parkkari 1,2,3,4,5

Editor—On the basis of our published data MacGregor et al computed estimates of genetic variance in liability to osteoporotic fractures. Our original manuscript had the same modelling analysis (table), but after a recommendation by a reviewer and the BMJ's editorial committee we omitted the modelling part of the study from the paper.

Table.

Model fitting for data on osteoporotic fractures among monozygotic and dizygotic twin pairs of Finnish twin cohort

Model Proportion of variance accounted for by:
χ2 value P value Akaike's information criterion2-150
Additive genetic effects (A) Non-additive genetic effects (D) Shared environmental effects (C) Unique environmental effects (E)
Men
 E 1.000 15.28 0.009 5.28
CE 0.216 0.784 7.22 0.13 −0.78
AE 0.347 0.653 3.28 0.51 −4.72
ACE 0.347 0.000 0.653 3.28 0.35 −2.72
ADE 0.000 0.398 0.602 1.83 0.61 −4.17
Women
 E 1.000 26.68 0.00 8.44
CE 0.260 0.740 0.57 0.97 −7.44
AE 0.367 0.633 1.35 0.85 −6.45
ACE 0.146 0.168 0.686 0.10 0.99 −5.91
ADE 0.367 0.000 0.633 1.35 0.72 −4.65
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2-150

Combines information on statistics of goodness of fit (the lower the χ2 value the better the fit) and simplicity of model (the best model usually being the one with the lowest value). 

MacGregor et al's interpretation of the results of the modelling differs from ours. We emphasise three points. Firstly, no matter what model is used to examine our data, the liability to osteoporotic fracture has a large environmental component (always ⩾60%) in both sexes. This is not clearly pointed out by MacGregor et al.

Secondly, we do not want to say that “genetic factors are of only minor importance in explaining the population occurrence of osteoporotic fracture”; we want to say that they are not strongly related to it. We thus want to draw attention to the fact that although genetic factors have a dominant role in explaining interindividual variation in bone density, the result is quite different (that is, unshared environmental effects become dominant) when the end point is changed from bone tissue to fractures, the true end point of the entire osteoporosis problem.

Thirdly, in women MacGregor et al highlight the AE model (the only contribution to risk of fracture is from genetic and unique environmental factors), in which genetic factors account for about 36% of the variance in liability to fracture, but they ignore the fact that the CE model (includes no genetic effects to explain twin similarity in liability to fracture) gave a better fit to the data. It has to be remembered that the statistical power of the study was not sufficient to differentiate between these competing explanations. Clearly, more incident cases are needed for more definitive conclusions.

Finally, we agree with MacGregor et al that there may well be differences in the nature of the genetic risk of osteoporotic fracture between men and women and at different body sites. Further follow up of our cohort and examination of the situation in other populations are thus needed.

With regard to Nemetz and Pena's letter, analysis of “silent” vertebral fractures will not change the result of the clinically more important non-vertebral fractures. We do not fully agree with the authors' statement that bone density is a key predictor of osteoporotic fractures. Many recent epidemiological studies indicate that falling is the strongest single predictor of these fractures, and bone mineral density is an independent predictor of only moderate importance. When this fact becomes more widely recognised, the framework of fracture prevention will become shifted more appropriately—towards preventing falls in elderly people.

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