Kirk Midkiff

The US postmarketing surveillance study of adult osteosarcoma and teriparatide: Study design and findings from the first 7 years

The Osteosarcoma Surveillance Study, an ongoing 15‐year surveillance study initiated in 2003, is a postmarketing commitment to the United States (US) Food and Drug Administration to evaluate a potential association between teriparatide, rhPTH(1–34), a recombinant human parathyroid hormone analog (self‐injectable medication to treat osteoporosis), and development of osteosarcoma in response to a finding from preclinical (animal) studies. Incident cases of primary osteosarcoma diagnosed in adults (aged ≥40 years) on or after January 1, 2003, are identified through population‐based state, regional, and comprehensive cancer center registries in the US. Information on possible prior treatment with teriparatide, on demographics, and on risk factors is ascertained by patient or proxy telephone interview after patient consent. Between June 2004 and September 30, 2011, 1448 cases (diagnosed 2003 to 2009) were identified by participating cancer registries (estimated to be 62% of all adult cases in the US for that time period); 549 patients or proxies were interviewed. Interviewed patients were similar to noninterviewed patients with regard to mean age, sex, race, and geographical distribution and tumor type and site of tumor. Mean age of those interviewed was 61 years, 46% were female, 86% were white, and 77% were alive when the case was reported to the study investigators. Data collected in the study provide descriptive information on a large number of adults with osteosarcoma, an uncommon malignant bone tumor. After 7 years of the study, there were no osteosarcoma patients who had a prior history of teriparatide treatment. Thus, approximately halfway through this 15‐year study, the study has not detected a pattern indicative of a causal association between teriparatide treatment and osteosarcoma in humans.

Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study

Limited information from spontaneous reports and results of two case‐control studies raised concern about the cardiotoxicity of oral domperidone therapy. This case‐control study nested in a retrospective cohort evaluated the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non‐users of these medications.

Prevalence of lower urinary tract symptoms and prostate enlargement in the primary care setting.

Purpose:  Men with lower urinary tract symptoms (LUTS) from benign prostatic hyperplasia often do not discuss their symptoms with their primary care physicians (PCPs). The primary objectives of this study were to estimate the prevalence of LUTS, prostate enlargement, and prostate‐specific antigen (PSA)  ≥ 1.5 ng/ml in men visiting their PCP and to assess patients’ intent to discuss LUTS with their PCP.

The experience of accommodating privacy restrictions during implementation of a large‐scale surveillance study of an osteoporosis medication

To explore whether privacy restrictions developed to protect patients have complicated research within a 15‐year surveillance study conducted with US cancer registries.

Challenges in studying very rare cancer outcomes and infrequent exposures: example of teriparatide and osteosarcoma

When preclinical toxicology studies show a clear and doserelated association between a medication exposure and a specific tumor type, an obvious question is, what will happen in humans? Regulatory agencies often respond by requiring additional studies before approval or a safety study to address the possible medication-outcome association in the postmarketing environment. However, if the medication is not commonly used, and the tumor rarely occurs in the general population, the probability of being able to confirm anything other than a very large increase in risk in a treated population is low. For the symposium described in the Pinheiro et al. article in this issue, we illustrated this type of challenge using a program of research relating to teriparatide; we offer some observations here. Teriparatide, a recombinant human parathyroid hormone analog, is an osteoanabolic used to increase bone mass for treatment of osteoporosis in specific populations with high fracture risk. This mechanism differs from other medications that aim to reduce bone resorption and turnover. In a clinical study of postmenopausal women, among 1326 women with a baseline and follow-up radiograph, researchers demonstrated a 65% reduction in new vertebral fractures in the teriparatide-treated group (5%) using the currently marketed dose compared with the placebo group (14%) [1]. Although not measured as outcomes in the clinical trials, vertebral fractures in general have been associated with increased short-termmortality, morbidity, and health care resource use [2]. In one 2-year (near-lifetime) preclinical study, in rats-administered teriparatide doses that created systemic exposures 3 to 60 times greater than that in humans, researchers found a dose-dependent increase in the incidence of osteosarcoma [3]. Subsequent studies demonstrated a “no-effect” dose in rats [4], and no bone tumors emerged in a long-term study of cynomolgus monkeys [5]. In addition, no cases emerged in humans in the clinical trial experience of over 2800 individuals; however, the U.S. product label of teriparatide contains a black boxwarning about the potential risk of osteosarcoma and recommends use in restricted populations and a treatment duration of no more than 2 years [6]. A published review of safety of teriparatide after 10 years of use concluded that no new safety issues had emerged that were not observed in clinical trials, and that the risk of osteosarcoma remained theoretical [7]. However, actual product use is relatively uncommon, with fewer than 40,000 patients prescribed Forteo (teriparatide) in Medicare part D in 2013 of 35million patients enrolled [8]. Osteosarcoma in humans is a primary malignant bone tumor with an incidence of 4.2 per million for those aged 60 years andmore [9]. Known risk factors are few, and most cases are diagnosed in patients without identified risk factors [10].

Comments on Bang et al.: The impact of recombinant parathyroid hormone on malignancies and mortality: 7 years of experience based on nationwide Danish registers

Dear Editor, An article by U. C. Bang, L. Hyldstrup, and J. E. B. Jensen in the February 2014 issue of Osteoporosis International evaluated the incidence of cancer and mortality in osteoporotic patients treated with recombinant parathyroid hormone analogs (rPTH), including the incidence of osteosarcoma, a rare bone cancer [1]. The evaluation of osteosarcoma is particularly important because of the prior finding of an increased risk of primary osteosarcoma in rats treated with rPTH [2–4]. We have been researching this topic in humans through epidemiologic studies of teriparatide since 2002, including a study referenced in the article. We need to highlight a key methodologic problem in the Bang et al. research because it has important implications for future epidemiologic studies of osteosarcoma. The outcome measure evaluated by the investigators as reported in the paper bears little relationship to primary osteosarcoma, the subject of the rPTH signal. The study used ICD-10 codes C40-C41 (malignant neoplasm of bone and articular cartilage of limbs) identified from inpatient and outpatient discharge records in the Danish National Patient Registry. Even considering the exclusion of patients with cancer prior to initiation of rPTH therapy, the codes used to define osteosarcoma would have captured many types of tumors located in the bone, not just primary osteosarcoma. In fact, the incidence of osteosarcoma is well established in the USA and European countries as approximately 2–4 cases per 1 million person-years [5]. The use of the imprecise ICD-10 category of C40-C41 may explain the very high incidence of “osteosarcoma” observed in the comparison cohort in the Bang paper: 1 per 10,000 person-years. Identification of osteosarcoma requires histologic confirmation. In our study of primary osteosarcoma, we used 12 categories in the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), that represent sarcoma that produces osseous matrix, irrespective of anatomical location [6]. Information on histologic confirmation and appropriate tumor categorization using these codes is available from the Danish Cancer Registry, which includes the entire population of Denmark and would have been a more appropriate source for outcome ascertainment in this study [7]. It is important to use precise outcome definitions and ascertainment measures in drug safety studies using secondary data sources. Calculation of incidence rates and effect measures based on overly broad code groups can obscure a true relationship between a specific outcome and drug. In the Bang et al. study, we are reassured because no cases, even using the broad category, were observed in the patients receiving rPTH.

Studying Cancer as an Adverse Outcome from Nononcological Therapies: Review of the Food and Drug Administration's Postmarketing Commitment Database (Meeting Abstract

Background: Sudden discontinuation of some antihypertensive agents such as beta-blockers and centrally acting antihypertensive agents are associated with increased risk of acute coronary events. Objectives: The aim of this study was to assess the association between discontinuation of different antihypertensive agents and the risk of acute myocardial infarction (AMI). Methods: A nested case control study was performed in a cohort of antihypertensive drug users from the Utrecht Cardiovascular Pharmacogenetics (UCP) database. Within this cohort, patients who were hospitalized for first AMI were considered cases. Cases were matched (1 up to 4) to controls at the same AMI date (index date). Antihypertensive users were defined as current users if the index date fell within prescribed duration or as stoppers if this date fell outside the prescribed duration. According to recency of stopping, stoppers were divided into recent stoppers (≤90 days), intermediate-term stoppers (91-180 days), and longterm stoppers (>180 days). The study included only antihypertensive users who were specifically current users or stoppers of one antihypertensive agent. Logistic regression analysis was used to assess the association between the discontinuation of antihypertensive agents and the risk of AMI and to control for confounding. Results: We included 1245 cases and 4994 controls in our analysis. The risk of AMI was significantly increased with all stoppers of beta-blockers (adjusted OR: 1.54, 95%CI (1.25-1.90)), calcium channel blockers (CCBs) (adjusted OR: 2.25, 95%CI (1.53- 3.30)), and diuretics (adjusted OR: 1.76, 95%CI (1.24-2.48)) compared with current users. Moreover, the risk of AMI was significantly increased for longterm stoppers (beta-blockers, CCBs, angiotensinconverting enzyme inhibitors, and diuretics) and intermediate- term stoppers (beta-blockers and CCBs) versus current users. There was no difference in AMI risk between recent stoppers of antihypertensive agents versus current users. Conclusions: Discontinuation of antihypertensive agents increases the risk of AMI after more than 90 days of stopping. Adherence to antihypertensive agents plays an important role in reducing the risk of AMI in patients with hypertension.Background: It has been reported that patients with type 1 diabetes (T1DM) have a decreased lung function. Studies on the association of T1DM and asthma in children show controversial results. Objectives: The aim of this study was to quantify asthma medication use in children and adolescents with and without (reference cohort) T1DM 5 years before and after the onset of diabetes. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children (1. Modelling of Endpoint Postponement for All-Cause Mortality in Statin Trials Morten Rix Hansen, Anton Pottegård, Asbjørn Hróbjartsson, Per Damkier, René D Christensen, Kasper Søltoft Larsen, Malene EL Kristensen, Palle M Christensen, Jesper Hallas. Clinical Pharmacology, University of Southern Denmark, Odense, Denmark; Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark; The Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark; Research Unit for General Practice, University of Southern Denmark, Odense, Denmark. Background: The average postponement of the outcome event has been proposed as a novel method to present the magnitude of effect for preventive medications. This measure has been shown to have better agreement with patient preferences than conventional outcomemeasures, including the “number needed to treat” (NNT), possibly because it is more intuitively understood. For some interventions, it may also provide a better theoretical frame for how benefit is distributed among participants than the NNT measure. The aim of this study was to present a novel method for modelling endpoint postponement (EP) from trial data and compare it with the usual approach of measuring the area between survival curves. We also present a formalized meta-analysis of modelled EP for all-cause mortality in statin trials. Methods: We identified 17 placebo-controlled statin trials that fulfilled our inclusion criteria. Eleven of these presented Kaplan–Meier curves for all-cause mortality. Average EP was calculated as the area between Kaplan–Meier curves by counting pixels on magnified prints for these 11 trials. The modelled EP was computed for all trials on the basis of (1) hazard ratio, relative risk or odds ratio; (2) the cumulative event rate in the untreated group; and (3) the trial’s running time. The underlying assumption was that the mortality was reasonably stable within the trials’ running time. The modelled EP was subjected to a meta-analysis, using inverse variance weighting in a random effect model. Results: EPswere generally small for estimates based on pixel-counting, 10 and 27days for trials both primary and secondary intervention that typically ran over 1.9– 6.1years. The modelled EPs varied between 2 and 34days. The difference between modeled EP and EP based on pixel-counting was between 8 and 12days. The results of the meta-analyses will be presented at the meeting. Conclusions: Based on these trial data, statin treatment results in a surprisingly small gain in average survival. Our modelled EP estimates agreed reasonably with EPs based on pixel-counting. The modeled EP is amenable to meta-analyses and may be a useful approach to presenting the benefit of preventive treatment. 2. Permanent User Bias in Case–Crossover Studies in Pharmacoepidemiology Jesper Hallas, Shirley V. Wang, Joshua J. Gagne, Sebastian Schneeweiss, Anton Pottegård. Clinical Pharmacology, University of Southern Denmark, Odense C, Denmark; Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Background: In pharmacoepidemiology, the case– crossover design is based on cases that have contrasting drug exposure at the time of an event and at a reference time in the past. If the drug in question should be taken permanently, only certain exposure patterns will occur. These patients cannot be unexposed at the event time and exposed at the reference time, while the opposite pattern can occur if the drug was initiated recently. The resulting odds ratio (OR) would thus be biased upward. As many drugs have a subpopulation of permanent users, this bias might pervade many case–crossover analyses of drug effects. Objectives: The aims of this study were to demonstrate this “permanent user bias” and to evaluate whether it can be remedied by including a control group (case–time–control design). Methods: Using nationwide Danish data resources, we conducted case–crossover and case–time–control analyses for combinations of three exposures that are