ContextKnee osteoarthritis (OA) is a leading cause of disability in older persons.
Few risk factors for disease progression or functional decline have been identified.
Hip-knee-ankle alignment influences load distribution at the knee; varus and
valgus alignment increase medial and lateral load, respectively.ObjectiveTo test the hypotheses that (1) varus alignment increases risk of medial
knee OA progression during the subsequent 18 months, (2) valgus alignment
increases risk of subsequent lateral knee OA progression, (3) greater severity
of malalignment is associated with greater subsequent loss of joint space,
and (4) greater burden of malalignment is associated with greater subsequent
decline in physical function.Design and SettingProspective longitudinal cohort study conducted March 1997 to March
2000 at an academic medical center in Chicago, Ill.ParticipantsA total of 237 persons recruited from the community with primary knee
OA, defined by presence of definite tibiofemoral osteophytes and at least
some difficulty with knee-requiring activity; 230 (97%) completed the study.Main Outcome MeasuresProgression of OA, defined as a 1-grade increase in severity of joint
space narrowing on semiflexed, fluoroscopically confirmed knee radiographs;
change in narrowest joint space width; and change in physical function between
baseline and 18 months, compared by knee alignment at baseline.ResultsVarus alignment at baseline was associated with a 4-fold increase in
the odds of medial progression, adjusting for age, sex, and body mass index
(adjusted odds ratio [OR], 4.09; 95% confidence interval [CI], 2.20-7.62).
Valgus alignment at baseline was associated with a nearly 5-fold increase
in the odds of lateral progression (adjusted OR, 4.89; 95% CI, 2.13-11.20).
Severity of varus correlated with greater medial joint space loss during the
subsequent 18 months (R = 0.52; 95% CI, 0.40-0.62
in dominant knees), and severity of valgus correlated with greater subsequent
lateral joint space loss (R = 0.35; 95% CI, 0.21-0.47
in dominant knees). Having alignment of more than 5° (in either direction)
in both knees at baseline was associated with significantly greater functional
deterioration during the 18 months than having alignment of 5° or less
in both knees, after adjusting for age, sex, body mass index, and pain.ConclusionThis is, to our knowledge, the first demonstration that in primary knee
OA varus alignment increases risk of medial OA progression, that valgus alignment
increases risk of lateral OA progression, that burden of malalignment predicts
decline in physical function, and that these effects can be detected after
as little as 18 months of observation.

/pdf/the-role-of-knee-alignment-in-disease-progression-and-2wtke3c7b3.pdf

The Role of Knee Alignment in Disease Progression and Functional Decline in Knee Osteoarthritis

ContextProton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps.ObjectiveTo determine the association between PPI therapy and risk of hip fracture.Design, Setting, and PatientsA nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed.Main Outcome MeasureThe risk of hip fractures associated with PPI use.ResultsThere were 13 556 hip fracture cases and 135 386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons).ConclusionLong-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.

/pdf/long-term-proton-pump-inhibitor-therapy-and-risk-of-hip-57d6d3occr.pdf

Long-term proton pump inhibitor therapy and risk of hip fracture.

Mevalonate pathway: a review of clinical and therapeutical implications.

Purpose
Recent observational studies suggest that various drugs are remarkably effective at reducing morbidity and mortality. These cohort studies used a flawed approach to design and data analysis which can lead to immortal time bias. We describe the bias from 20 of these studies and illustrate it by showing that unrelated drugs can be made to appear effective at treating cardiovascular disease (CVD).

Methods
The illustration used a cohort of 3315 patients, with chronic obstructive pulmonary disease (COPD), identified from the Saskatchewan Health databases, hospitalised for CVD and followed for up to a year. We used the biased approach to assess the effect of two medications, namely gastrointestinal drugs (GID) and inhaled beta-agonists (IBA), both unknown to be effective in CVD, on the risk of all-cause mortality. We also estimated these effects using the proper person-time approach.

Results
Using the inappropriate approach, the rates ratios of all-cause death were 0.73 (95%CI: 0.57–0.93), with IBA and 0.78 (95%CI: 0.61–0.99), with GID. These rate ratios became 0.98 (95%CI: 0.77–1.25) and 0.94 (95%CI: 0.73–1.20), respectively, with the proper person-time analysis.

Conclusions
Several recent observational studies used a flawed approach to design and data analysis, leading to immortal time bias, which can generate an illusion of treatment effectiveness. Observational studies, with surprising beneficial drug effects should be re-assessed to account for this source of bias. Copyright © 2007 John Wiley & Sons, Ltd.

Immortal time bias in observational studies of drug effects

Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular and coronary heart diseases. Recently, a multifaceted action in different physiological and pathological conditions has been also proposed for statins, beyond anti-inflammation and neuroprotection. Statins have been shown to act through cholesterol-dependent and -independent mechanisms and are able to affect several tissue functions and modulate specific signal transduction pathways that could account for statin pleiotropic effects. Typically, statins are prescribed in middle-aged or elderly patients in a therapeutic regimen covering a long life span during which metabolic processes, aging, and concomitant novel diseases, including cancer, could occur. In this context, safety, toxicity, interaction with other drugs, and the state of health have to be taken into account in subjects treated with statins. Some evidence has shown a dichotomous effect of statins with either cancer-inhibiting or -promoting effects. To date, clinical trials failed to demonstrate a reduced cancer occurrence in statin users and no sufficient data are available to define the long-term effects of statin use over a period of 10 years. Moreover, results from clinical trials performed to evaluate the therapeutic efficacy of statins in cancer did not suggest statin use as chemotherapeutic or adjuvant agents. Here, we reviewed the pharmacology of the statins, providing a comprehensive update of the current knowledge of their effects on tissues, biological processes, and pathological conditions, and we dissected the disappointing evidence on the possible future use of statin-based drugs in cancer therapy.

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

bral fractures, the ORs were 1.01 (95% CI, 0.80-1.27), 0.59 (95% CI, 0.31-1.13), and 1.15 (95% CI, 0.62-2.14), respectively. Relative to nonuse, a statin dosage of less than 20 mg/d (standardized to simvastatin) was associated with an adjusted OR of fracture of 1.13 (95% CI, 0.96-1.33); this OR was 1.07 (95% CI, 0.82-1.38) at dosages of 20 to 39.9 mg/d and 0.85 (95% CI, 0.47-1.53) at dosages of 40 mg/d or more. The adjusted OR was 0.71 (95% CI, 0.50-1.01) for statin use durations of 0 to 3 months, 1.31 (95% CI, 0.87-1.95) for durations of 3 to 6 months, 1.14 (95% CI, 0.82-1.58) for durations of 6 to 12 months, and 1.17 (95% CI, 0.99-1.40) for durations of more than 12 months. Conclusion In this study, use of statins at dosages prescribed in clinical practice was not associated with a reduction in risk of fracture. JAMA. 2001;285:1850-1855 www.jama.com

https://jamanetwork.com/journals/jama/articlepdf/193727/joc01249.pdf

Sebastiaan Wegman

Papers

Use of statins and risk of fractures.

Use of Statins and Risk of Fractures