Primecuts – This Week in the Journals

October 16, 2018

By Jacob Teperman, MD

Peer Reviewed

This month, James P Allison and Tasuku Honjo shared the Nobel Prize for Physiology or Medicine for their contributions to the oncology world with their developments in immune checkpoint therapies.  Allison discovered CTLA-4 while Honjo was the first to work with PD-1.1 Their work has lead to the development of immunologics, most notably nivolumab, which is approved  for the treatment of advanced/metastatic melanoma, metastatic non small cell lung cancer, small cell lung cancer and advanced renal cell carcinoma2 to name a few.

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta analysis, and trial of sequential analysis (Lancet) [3]

Despite widespread use, vitamin D’s effect on fracture and bone density, in particular at high doses is unclear. This article attempted to clarify this via a systematic review of the literature. 81 randomized controlled trials were identified, 42 reporting fractures, 41 reporting falls as outcomes. These trials all compared vitamin d to either placebo, untreated controls or low dose supplementation. In pooled analyses, vitamin D supplementation did not affect total fracture risk with a relative risk (RR) 1[95% CI .93-1.07]. This was also shown to be true when high dose vitamin D (greater than 800 IU) was compared to low dose vitamin d. This lack of clinical significance permeated into the bone mineral density comparisons over a 5-year period (-.16-.76).  Given that this was a systematic review of Meta analysis, one may be quick to brush off these findings. However the trial of sequential analysis performed helps to diminish type I and II systematic errors. This study, although limited, reveals evidence that vitamin D supplementation may not be as helpful as previously thought. However, given that vitamin D is associated with few negative side effects, the implications of this study may not rapidly alter management.

Receipt of Overlapping Opioid and Benzodiazepine Prescriptions among Veterans Dually Enrolled in Medicare Part D and the Department of Veterans Affairs (Annals of Internal Medicine) [4]

Given the current opioid crisis, opioids and benzodiazepine prescriptions are under particular scrutiny. Although there are many tools in place to prevent duplicate prescriptions, such as the I-STOP database, many populations are still at risk for overlapping prescriptions. This study evaluated one such group, veterans receiving care both within the VA as well as through Medicare Part D. All veterans enrolled in these two entities who filled at least 2 opioid prescriptions in 2013 were evaluated (368,891). Approximately 51% of these veterans received prescriptions from both the VA and through Medicare (termed dual coverage). Overlap was defined using the pharmacy quality alliance definition. The results demonstrated that dual coverage patients received more overlapping prescriptions compared to the VA only group and the Medicare only group(23.1% vs. 17.3% adjusted RR 1.27 [95% CI 1.24-1.30], and 23.1% vs. 16.5% aRR 1.12 [95% CI 1.10-1.14]). This trend remained significant when evaluating high dose opioid and benzodiazepine prescription overlap. Despite the significant findings, this study is limited by its lack of generalizability given this specific patient population and lack of evaluated clinical outcomes such as morbidity and mortality. However, the implications, notably that this population is at an increased risk, should not be taken lightly.

Analysis of Diagnostic Test Ordering Habits Among Internal Medicine Residents (JAMA) [5]

Having worked on a medicine floor at a hospital, one might presume that the number of tests ordered varies from team to team, resident to resident. But is this true? A few studies have shown this in the past6,7, but a group at New York Presbyterian/Weill Cornell Medical College tackled this issue. They compared the number of tests ordered by each of the 139 residents over the 2016-2017 academic year. What they found was that the resident who ordered the most tests ordered approximately 7 times the number as the one who ordered the least (13,604 vs. 1,870). A linear regression analysis demonstrated that the greater the pgy level, the fewer tests were ordered. A major limitation postulated by the authors is that the results could be related to the flow of the hospital (notably that the interns are placing more of the orders). Regardless, this study brings up the question of inter-resident variability. That despite a similar training curricula, there exists vast differences in the way medicine is practiced. Although the outcomes of these variations are not quantified in this study, it makes sense to be thoughtful about each test that is ordered, and to limit phlebotomy/radiology only to what is necessary instead of simply ordering daily labs.

Bisphosphonates for Patients Diagnosed with Multiple Myeloma (JAMA) [8]

Bisphosphonates are often used in multiple myeloma. There is evidence for their effectiveness in hypercalcemia9, however what is the evidence for their effect on mortality or preventing pathologic fractures? JAMA decided to review this topic in their clinical evidence synopsis section. A monthly section where they concisely examine systematic reviews which they find of particular importance to clinicians. They assessed a Cochrane review of 24 randomized controlled trials from 1980-2013. These studies compared bisphosphonates to either each other, placebo, or no treatment, with primary outcomes of mortality, vertebral and nonvertebral fractures. The results demonstrated no mortality benefit when compared with placebo RR .9[95% CI .76-1.07]. However they were associated with a lower risk of pathologic fractures RR .74[95% CI .62-.89].  Although this is a Meta analysis, it does demonstrate evidence for continued use of bisphosphonates in multiple myeloma outside of their known benefit on calcium levels. A limitation of this study is that there was no direct comparison of the two commonly used bisphosphonates in the US, zoledronic acid and pamidronate. Zoledronic acid has been shown to be more effective in hypercalcemia of malignancy9, but no study evaluates the two head to head with these important clinical endpoints in mind.


More Youth Vaccinated for HPV (JAMA) [10]

In 2017, 48.6 % of adolescents had completed the hpv vaccine series. This is a 5% increase from the previous year, a step in the right direction.

Short-Term Prognosis of Myocardial Injury, Type 1 and Type 2 Myocardial Infarction in the Emergency Unit (American Journal of Medicine) (11)

In a large ED population, surprisingly all cause mortality was found to be higher in type 2 myocardial infarctions as well as non-ischemic myocardial injury patients when compared to those with type I MIs.

Phase 2 trial of Selective Tyrosine Kinase 2 inhibition in Psoriasis (NEJM) [12]

Selective inhibition of tyrosine kinase 2 with a new oral agent BMS-986165 led to greater clearing of psoriasis when compared to placebo (anywhere from 39-75% depending on the dosage used vs. 7% in the placebo arm).

Dr. Jacob Teperman is a lst-year resident at NYU Langone Health

Peer reviewed by Neil Shapiro, editor-in-chief, Clinical Correlations

Image courtesy of CNBC


  1. Nivolumab FDA package insert. Initial US approval 2014.
  1. Bolland M, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. The Lancet Diabetes & Endocrinology.Published online October 04, 2018. DOI:10.1016/S2213-8587(18)30265-1
  1. Carico R, Zhao X, Thorpe CT, Thorpe JM, Sileanu FE, Cashy JP, et al. Receipt of Overlapping Opioid and Benzodiazepine Prescriptions Among Veterans Dually Enrolled in Medicare Part D and the Department of Veterans Affairs: A Cross-sectional Study. Ann Intern Med. [Epub ahead of print ] doi: 10.7326/M18-0852
  1. Geleris JD, Shih G, Logio L. Analysis of Diagnostic Test Ordering Habits Among Internal Medicine Residents. JAMA Intern Med.Published online October 08, 2018. doi:10.1001/jamainternmed.2018.3519
  1. O’Brien  DK, Flood  J, Wesley  R.  Resident test ordering patterns. Fam Pract Res J. 1987;7(1):42-50.PubMedGoogle Scholar
  1. Dine  CJ, Bellini  LM, Diemer  G,  et al.  Assessing correlations of physicians’ practice intensity and certainty during residency training. J Grad Med Educ. 2015;7(4):603-609. doi:10.4300/JGME-D-15-00092.1
  1. Mhaskar R, Djulbegovic B. Bisphosphonates for Patients Diagnosed With Multiple Myeloma. JAMA.2018;320(14):1483–1484. doi:10.1001/jama.2018.13773.
  1. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-67.
  1. Kuehn B. More Youth Vaccinated for HPV. JAMA.2018;320(14):1426. doi:10.1001/jama.2018.14296
  1. Short-Term Prognosis of Myocardial Injury, Type 1, and Type 2 Myocardial Infarction in the Emergency Unit. Putot, Alain et al. The American Journal of Medicine , Volume 131 , Issue 10 , 1209 – 1219.
  1. Papp K, Gordon K, Thaçi D, et al. Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med. 2018;379(14):1313-1321.



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