Genetic studies of osteoporosis: A rethink required

It has been 10 years since the seminal paper by Morrison and colleagues reporting the association of alleles of the vitamin D receptor and bone density [1], a paper which arguably kick-started the study of osteoporosis genetics. Since that report there have been literally thousands of osteoporosis genetic studies published, and large numbers of genes have been reported to be associated with the condition [2]. Although some of these reported associations are undoubtedly true, this snow-storm of papers and abstracts has clouded the field to such a great extent that it is very difficult to be certain of the veracity of most genetic associations reported hereto. The field needs to take stock and reconsider the best way forward, taking into account the biology of skeletal development and technological and statistical advances in human genetics, before more effort and money is wasted on continuing a process in which the primary achievement could be said to be a massive paper mountain. I propose in this review that the primary reasons for the paucity of success in osteoporosis genetics has been: •the absence of a major gene effect on bone mineral density (BMD), the most commonly studied bone phenotype; •failure to consider issues such as genetic heterogeneity, gene–environment interaction, and gene–gene interaction; •small sample sizes and over-optimistic data interpretation; and •incomplete assessment of the genetic variation in candidate genes studied