Prescribing of anti-osteoporotic therapies following the use of Proton Pump Inhibitors in general practice B. McGowan, K. Bennett, J. Feely Department of Pharmacology & Therapeutics, Trinity Centre for Health Sciences, St James s Hospital, Dublin
Background Approximately 11% of the Irish population are over the age of 65 (468,000).By 2031 this proportion will increase to 18% i.e to over 1 million older people. International literature suggests that 1/3 of women and 1/5 of men over 50yrs suffer from osteoporosis. If we apply these rates in Ireland to the age grp 65 and over, it is estimated that approx. 84,567 women and 39,420 men have osteoporosis (N=123,987). Osteoporosis is a skeletal disease characterised by low bone density with a resulting increase in bone fragility and therefore increased risk of fracture. In women, the one in six lifetime risk of hip fracture is greater than the one in nine risk of developing breast cancer.
Osteoporosis Fractures of the hip, vertebral body, pelvis and distal forearm have generally been considered as the typical osteoporotic fractures. Of all fractures hip fractures can often have the most devastating consequences on patients. The mortality rate within the first twelve months following the fracture can be as high as 20%. Among patients who survive the trauma of the fracture, 1 in 5 will be admitted to a nursing home.
Osteoporosis (cont d) Approx 130,000 individuals aged 65 and over fall each year > of these about 108,000 do not seek medical attention, > about 1,500 are admitted to hospital for other injuries due to falls > almost 7,000 are admitted to hospital for fractures, utilising 5.2% of the 1.8 million hospital bed days used by older people. Mean length of hospital stay for colles fracture is 4.2 days and for hip fracture 17.1 days. The results of the Irish Burden of Illness Study shows that in financial terms fall related injuries in older people cost 402 million to the economy. Ref: Strategy to Prevent Falls and Fractures in Ireland s Ageing Population by the National Council on Ageing and Older People Jan 2008
Oral Bisphosphates Oral bisphosphonates represent a significant advance in the management of osteoporosis in the past ten years, with results of clinical trials demonstrating reductions in : - the risk of vertebral fractures as high as 40-50% - and in non-vertebral fractures between 20-40%. They are considered first line therapy for the prevention of osteoporosis in postmenopausal women and the prevention and treatment of corticosteroid-induced osteoporosis (CIO). Antiresorptive agents increase BMD and decrease fracture risk by reducing bone turnover and restoring the balance between bone resorption and bone formation
The effects of different therapeutic agents on bone mineral density (BMD). A number of studies have identified that certain drug groups may have a beneficial effect on bone mineral density subsequently reducing the risk of hip fractures such as : > statins, > thiazides, > beta blockers > Ca Channel Blockers > Angiotension 11 rec antagonists and > Ace Inhibitors. In contrast an increasing number of studies are showing that drug groups such as: > corticosteroids,> antiepileptic drugs, >antidepressants (Selective Serotonin Reuptake Inhibitors), Antiparkinson> Antipsychotics> Anxiolytics,> excess use of thyroxine, > NSAIDS and >long term use of Proton Pump Inhibitors may increase the risk of hip fractures.
Proton Pump Inhibitors The Proton Pump Inhibitors inhibit the production and intragastric secretion of hydrochloric acid which is believed to be an important mediator of calcium absorption in the small intestine. Recent studies have suggested that the use of PPI therapy is associated with hip fracture and other osteoporotic fractures.
Previously published studies Yu-Xiao Yang, James D. Lewis, Solomon Epstein. David C. Metz. Long-term Proton Pump inhibitor Therapy and Risk of Hip Fracture. JAMA, December 27, 2006-Vol 296, No. 24. Laura E. Targownik, Lisa M. Lix, Heather J. Prior, Stella Leung, William D. Leslie, Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008 August 12; 179(4): 319-326 P.Vestergaard, L. Rejnmark, L. Mosekilde. Proton Pump Inhibitors, Histamine D2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture. Calcified Tissue International. 2006 15 August; 79: 76-83.
Aims of the study: To determine the association between the prescribing of osteoporotic type medication (in particular bisphosphonates ) in patients receiving proton pump inhibitors. To determine if this association varied depending on dose and duration of PPI therapy.
Methodology: The cohort study used the Irish Health Services Executive (HSE) Primary Care Reimbursement Services (PCRS) pharmacy database. which contains prescription information for 1.2 million people in Ireland (30% of the population). It covers approximately 73% of all prescriptions issued and approximately 70% of the cost of medications. While the database is not linked to diagnosis, the use of bisphosphonates is specific for osteoporosis in the PCRS scheme as prescriptions for other conditions are reimbursed under other schemes within the Irish Healthcare system.
Adjusted odds ratios (OR and 95% CIs) were determined by logistic regression, adjusting for age, gender and other medications which potentially increase and decrease bone mineral density. Methodology cont d Data from 2003 was used as the run-in period where all patients who were prescribed a PPI or osteoporotic type medication were identified and excluded from the study. Those aged 55 years and over were included. Individuals were classified as new PPI users if they initiated PPI therapy after 2003, and those not receiving PPI therapy after 2003 were the controls. Subsequent prescribing of anti-osteoporotic therapy was considered from 2004 2007 in both PPI user and control groups.
Study Cohort N= 896,919 Patients Excluded N= 27,185 N=869,734 All age grps N= 442,341 Over 55 yr agegrp PPI users N= 209,175 Non PPI users N=233,166 Subsequent osteo therapy N=42,589 (20.4%) Subsequent osteo Therapy N=31,779 (13.6%)
Table 1: Prescribing of anti-osteoporotic type meds subsequent to the prescribing of PPI therapy, results adjusted for Age and Gender Variable OR 95% CI P-Value PPI users vs Non-users 1.69 [1.66-1.72] <.0001 Age band 65-69 yrs vs 55-64yrs 70-74yrs vs 55-64yrs 75 + vs 55-64yrs 1.25 1.47 1.31 [1.21-1.28] [1.44-1.51] [1.28-1.34] Gender Female vs Male 4.31 [4.22-4.39]
Table 2: Prescribing of anti-osteoporotic type meds subsequent to the prescribing of PPI therapy, results adjusted for Age and Gender and meds that increase or decrease BMD Variable OR 95% CI P-Value PPI users vs Non-users 1.28 [1.25-1.29] <.0001 Age band 65-69 yrs vs 55-64yrs 70-74yrs vs 55-64yrs 75 + vs 55-64yrs 1.22 1.47 1.40 [1.18-1.26] [1.43-1.51] [1.36-1.43] Gender Female vs Male 4.43 [4.33-4.52]
Results: Duration of PPI therapy Duration of OR 95% CI P value therapy 0 3 months 0.71 0.69-0,73 3-6 months 1.10 1.06-1.15 <.0001 6-12 months 1.34 1.30-1.39 <.0001 12-18 months 1.58 1.52-1.65 <.0001 18-24 months 1.71 1.64-1.79 <.0001 > 24 months 1.99 1.94-2.03 <.0001
Results: Dose response of PPI therapy Dose of PPI in ddds OR 95% CI 0-90 ddds 0.90 0.85-0.95 >90 <=180ddds 1.26 1.18-1.34 >180 <=360ddds 1.32 1.24-1.40 >360 <=540ddds 1.46 1.37-1.56 >540 <=720ddds 1.54 1.44-1.65 >720 1.68 1.60-1.77
Bisphosphonate prescribing after the prescribing of PPI therapy adjusted for age gender and other medications ORs 95% CI PPI users followed by Bisphos prscribing Agebands 65-69yrs vs 55-64yrs 70-74yrs vs 55-64yrs 75 + vs 55-64yrs 1.29 1.27-1.32 1.46 1.41-1.52 1.88 1.82-1.94 1.78 1.73-1.83 Gender Females Vs Males 5.10 4.96-5.24
Main Findings The results of this study provide significant evidence of an association between the use of PPIs and subsequent prescribing of anti-osteoporotic agents in the general population. The response identified remains statistically significant even when adjusted for age and gender. When adjustments were made for other pharmacological confounders which have a known effect on bone mineral density, the OR decreased but still continued to be statistically significant.