Modulatory effect of farnesyl pyrophosphate synthase (FDPS) rs2297480 polymorphism on the response to long-term amino-bisphosphonate treatment in postmenopausal osteoporosis

ABSTRACT

Introduction: Polymorphisms of genes encoding enzymes of the mevalonate pathway could modulate the response to amino-bisphosphonate treatment in postmenopausal osteoporosis.

Research design and methods: A characterisation of 234 Danish osteoporotic postmenopausal women (as part of the Prospective Epidemiological Risk Factors study (PERF)), treated for at least 2 years with amino-bisphosphonates, with respect to the adenosine/cytosine (A/C) rs2297480 farnesyl pyrophosphate synthase (FDPS) gene polymorphism, was carried out by PCR-based enzymatic digestion and quantitative PCR allelic discrimination on genomic DNA extracted from blood leukocytes. The association between these polymorphism genotypes and the response of spine and femur bone mineral density (BMD) and of biochemical bone biomarkers to treatment with amino-bisphosphonates was statistically examined.

Results: FDPS polymorphism did not show any relationship to baseline spinal and femoral BMD in Danish postmenopausal women. BMD response to treatment with amino-bisphosphonates was similar in the AA and the AC genotypes, while the CC genotype showed a lower BMD response to 2-year-treatment with amino-bisphosphonates at all examined skeletal sites ( p = 0.60 at the spine and p = 0.59 at the femur). Interestingly, after 2 years of treatment the response of urinary Cross-laps to amino-bisphosphonates treatment was significantly ( p < 0.05) lower in the CC genotype when compared to both the AC and AA genotypes. Even the response of serum osteocalcin was lower in the CC genotype, but without reaching a statistical significance ( p = 0.65).

Conclusions: Danish postmenopausal women with osteoporosis bearing the homozygous CC genotype for rs2297480 FDPS polymorphism showed a decreased response of bone turnover markers to amino-bisphosphonate therapy, when compared to the heterozygous AC and to the homozygous AA genotypes. Further investigation on larger and different populations, together with polymorphism functional studies are required to confirm these data.

Key Words::

• Amino-bisphosphonates
• Bone Mineral Density (BMD)
• Bone turnover markers
• Farnesyl pyrophosphate synthase gene (FDPS)
• Gene polymorphisms

Acknowledgements

Declaration of interest: This work was performed with support from the MIUR 2003 ‘Genetics markers of osteoporosis in Italian population’ from the EU project ‘GENOMOS – Genetic markers for osteoporosis’ (QLRT-2001-02629); from the FIRB PNR 2001-2003 (protocol RBNE01C5S2) ‘Identification of genetic susceptibility to multifactorial diseases in the Italian population’ from the ISS 2003 SARA project n. 4AF/F10 ‘Correlation study between endocrine estrogenic activity and genetic polymorphisms’ from the Ente Cassa Di Risparmio Di Firenze, and from FIRMO (Fondazione Italiana Ricerca sulle Malattie dell’Osso) to MLB. All the authors are grateful to Mrs Debora Strigoli for the technical assistance.

All the authors declare they have no conflict of interest.

Notes

* Material reported in this article was previously presented at the Second International Meeting on Pharmacogenetics of Osteoarticular Disorders, Florence, Italy, 19 April 2008