Introduction

Periprosthetic osteolysis resulting in aseptic loosening is a leading cause for total hip arthroplasty (THA) failure. Individuals vary in their susceptibility to osteolysis, and it is thought that heritable factors contribute to this variation. We conducted two genome-wide association studies to identify genetic risk loci associated with osteolysis and genetic risk loci associated with time to prosthesis failure due to osteolysis.

Introduction: Bone phenotype, such as osteoarthritis (OA) pattern and development of osteolysis or heterotopic ossification (HO) after THA, may be governed by genetic and environmental factors. We investigated whether single nucleotide polymorphisms within the gene encoding secreted-Frizzled Related Protein-3, FRZB Arg200Trp and FRZB Arg324Gly influence bone phenotype.

Methods: Genomic DNA was extracted from 609 subjects at a mean of 11 years following cemented THA for idiopathic osteoarthritis. Pre-operative OA was defined using The American College of Rheumatology criteria and post operative HO after primary THA was assessed using Brooker’s classification

Results: For FRZB Arg200Trp, minor allele carriage (MAC) was greater in subjects with pre-operative pelvic osteophytes (n=267) versus those without osteophytes (n=34) (MAC 27.9% versus 6.3%, Fisher’s exact test p=0.037). There were no associations with other radiographic criteria of OA. MAC was also higher in HO+ve subjects (n=291) versus HO-ve subjects (n=341), (MAC 21.7% versus 12.0%, χ² test p=0.063). Finally MAC was 14.2% in osteolysis +ve subjects (n=268) and 21.7% in osteolysis –ve subjects (n=341) (χ² test p=0.041).

The adjusted odds ratios for pelvic osteophytes and HO with carriage of the rare FRZB 200 variant were 4.34 (1.01–18.7 p=0.048) and 1.64 (1.05 to 2.54, p=0.028) respectively. The adjusted odds ratio for osteolysis was 0.62 (0.38 to 0.99 p=0.049).

There were no bone phenotype associations with the FRZB Arg324Gly variants.

Discussion: Carriage of the FRZB 200Trp allele is positively associated with osteophyte and HO formation and negatively associated with osteolysis, suggesting this locus may be a marker for pro-osteoblastic activity.

In-vitro evidence suggests that wear debris can alter osteoblast function resulting in decreased bone matrix production and negative remodelling balance. FRZB encodes for Secreted Frizzled-Related Protein 3 which may play a role in bone formation and osteoarthritis. This study was undertaken to investigate whether the recently described single nucleotide polymorphisms (SNPs) at positions [+6] and [+109] of the FRZB gene are associated with osteolysis after THA.

Genomic DNA was extracted from 481 North European Caucasians at a mean of 12 years following cemented THA for idiopathic osteoarthritis. The control group consisted of 267 subjects and the osteolysis group 214 subjects. The [+6] and [+109] FRZB SNPs were genotyped using standard techniques.

For the FRZB [+6] SNP, the rare T allele was significantly over-represented in control versus the osteolysis group (χ² test for trend, p=0.02,). The odds ratio for osteolysis associated with carriage of the [+6] T-allele versus the [+6] C-allele was 0.58 (95%CI 0.36 to 0.94), p=0.03. The odds ratio for osteolysis associated with carriage of the [+109] G-allele versus the [+109] C-allele was 0.66 (0.38 to 1.12), p=0.15. A number of covariates have previously been described in this cohort and after adjustment for the effects of these covariates, the odds ratio for osteolysis with carriage of the [+6] T-allele was 0.69 (0.42–1.16).

We found that the FRZB [+6] T-allele is less common in subjects with osteolysis after THA versus controls, suggesting that allelic variants of genes associated with bone formation pathways may have a role in modulating the risk of osteolysis. However its loss of significance after correction for other factors suggests an interaction between this allele and other risk factors in osteolysis.