Hip fracture rates and bisphosphonate consumption in Spain. An ecologic study.

INTRODUCTION: Bisphosphonates are used worldwide to treat osteoporosis and, thus, to prevent fractures. Though they have been proven in clinical trials to avoid some fractures, their effectiveness in reducing hip fractures is unclear. The aim of the present study was to explore the relationship between bisphosphonate use and hip fracture trends in Spain. METHODS: For this purpose, an ecologic study spanning 2002 to 2008 was conducted in Spain. Consumption data were obtained from the Spanish Ministry of Health and Social Policy. The number of hip fractures was obtained from hospital discharges; annual hip fracture rates were determined and standardized using the Spanish 2002 population census. A linear regression was performed between fracture rate and use of bisphosphonates; R(2) and Pearson correlation coefficient were calculated. RESULTS: From 2002 to 2008, dispensed prescriptions of bisphosphonates in Spain increased from 3.28 to 17.66 DDD/1,000 inhabitants per day. In the same period, the crude hip fracture rate increased from 2.85 to 3.02 cases per 1,000 inhabitants older than 50 years; however, when age standardized rates were estimated, the rate declined from 2.85 to 2.79. Analyzed by sex, the standardized rate for men slightly increased from 1.45 to 1.48, while for women the rate significantly dropped from 4.00 to 3.91. CONCLUSION: A small effect of bisphosphonates on hip fracture rates can not be ruled out; however, other factors might partially explain this decline. Assuming this medication was the only cause for hip fracture rate reduction, the elevated medication cost to avoid a single hip fracture makes it necessary to explore less expensive interventions.

Relaxation gating of the acetylcholine-activated inward rectifier K+ current is mediated by intrinsic voltage sensitivity of the muscarinic receptor.

Normal heart rate variability is critically dependent upon the G-protein-coupled, acetylcholine (ACh)-activated inward rectifier K+ current, I(KACh). A unique feature of I(KACh) is the so-called 'relaxation' gating property that contributes to increased current at hyperpolarized membrane potentials. I(KACh) relaxation refers to a slow decrease or increase in current magnitude with depolarization or hyperpolarization, respectively. The molecular mechanism underlying this perplexing gating behaviour remains unclear. Here, we consider a novel explanation for I(KACh) relaxation based upon the recent finding that G-protein-coupled receptors (GPCRs) are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine (ACh) and pilocarpine (Pilo) manifest opposite voltage-dependent I(KACh) modulation. We show that Pilo activation of I(KACh) displays relaxation characteristics opposite to that of ACh. We explain the opposite effects of ACh and Pilo using Markov models of I(KACh) that incorporate ligand-specific, voltage-dependent parameters. Based on experimental and computational findings, we propose a novel molecular mechanism to describe the enigmatic relaxation gating process: I(KACh) relaxation represents a voltage-dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor.