Primecuts – This Week in the Journals

January 11, 2020

By Brandon Adelson, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized, Placebo-Controlled Study [1] 

Osteoarthritis is a major source of morbidity worldwide [2]. Structural changes associated with osteoarthritis progression include increased bone area and cartilage degradation through matrix protein breakdown [3]. Cathepsin K is a protease expressed in osteoclasts that is thought to be involved in cartilage degradation.

This randomized, double-blinded, placebo-controlled phase 2a study looked into the effects of a novel Cathepsin K inhibitor (MIV-711) among individuals with primary knee osteoarthritis. There were 240 participants across six European centers, with participants split into three groups. Group 1 (n=81) received 100mg daily of MIV-711, group 2 (n=82) received 200mg daily, and group 3 (n=77) received placebo for a 26-week period. The primary outcome was change in pain score on a numerical rating scale. Secondary outcomes included change in bone area on MRI, cartilage thickness and levels of collagen biomarkers.

The results showed that changes in pain score with MIV-711 were not statistically significant across the three groups. Bone area was statistically significant between the two treatment groups and placebo, while cartilage thinning was also lower in the 100mg group.

This study has many limitations. The first is its small sample size. Second, there is questionable clinical impact as there was no difference between pain scores across the groups, and it’s unclear if changes in bone area are of clinical importance. Nevertheless, this agent may serve to slow remodeling and should be studied in a larger population.

Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis [4]

Osteoporosis, the loss of bone mass and remodeling of bone architecture, becomes more prevalent in aging populations [5]. Vitamin D and calcium have long been studied in the prevention of osteoporotic fracture. Current society recommendations include combined supplementation as opposed to Vitamin D or calcium alone [6].

This systematic review and meta-analysis assessed how different levels of 25-hydroxyvitamin D and supplementation with calcium related to risk of osteoporotic fracture. Eleven observational studies, looking at the relation of Vitamin D levels to fractures, were chosen for review. Another 11 RCTs of Vitamin D and 6 RCTs of Vitamin D and calcium (compared to placebo or no treatment) were chosen for review. The primary outcomes were any fracture and hip fracture.

The analysis found that with each increase of Vitamin D level by 10ng/mL, the relative risk (RR) for any fracture was 0.93 (95% CI, 0.89-0.96) and the RR for hip fracture was 0.80 (95% CI, 0.75-0.86). The RCTs looking at Vitamin D supplementation vs. placebo/no treatment did not find a reduced risk of any fracture or hip fracture, but with combined supplementation vs. placebo/no treatment there was a RR of 0.94 (95% CI, 0.89-0.99) for any fracture and a RR of 0.84 (95% CI, 0.72-0.97) for hip fracture.

The dosing of Vitamin D in the studies varied greatly, which may confound the results. The authors also noted there were 2 RCTs in which very high annual dosing of Vitamin D actually increased the risk of fractures. Regardless, this analysis strongly suggests that combined supplementation of calcium and Vitamin D is beneficial for preventing osteoporotic fractures.

Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent [7]

Nephrogenic systemic fibrosis (NSF), characterized by skin and organ fibrosis, is an iatrogenic condition that can occur in patients with AKI or CKD stage 4/5 that are administered gadolinium agents [8]. Recently it was noted that not all gadolinium agents carry the same risk of NSF, however individual patient risk is not well characterized in the literature [9].

This study, a systematic review and meta-analysis, assessed the risk of NSF in patients with CKD stage 4 and 5 and who received group II gadolinium-containing contrast agents. Sixteen studies with a total of 4931 patients were included for review. Of the 4931 patients in the analysis, none developed NSF. The upper bound of the 2-sided 95% CI was 0.07%. Follow-up intervals for the studies ranged from 3 to 72 months.

While certain gadolinium-based contrast agents are contraindicated in CKD 4 and 5, this study suggests group II agents are likely safe for use, as reflected in the current American College of Radiology recommendations [10]. Additionally, the study determined that the group II agent that likely has the greatest safety margin is gadobenate dimeglumine. This was the agent used most commonly, with 3167 cases and no NSF). This review is likely beneficial for providers who would otherwise withhold indicated studies out of fear of NSF.


Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI [11] 

This study analyzed bronchoalveolar lavage (BAL) fluid from 51 patients with either confirmed or probable e-cigarette or vaping product use-associated lung injury (EVALI) and compared it to BAL fluid from 99 healthy subjects. Of the 51 EVALI patients, 48 (94%) had detectable levels of Vitamin E, while Vitamin E was not isolated from any of the healthy subjects. 94% of EVALI participants also had either THC/THC metabolites detectable in fluid, or reported vaping THC products 90 days before the onset of their illness. The delivery of Vitamin E through vaping seems to play an integral role in the development of injury, while the absence of most other toxicants in study samples is also notable.

The Von Willebrand Factor antigen to platelet ratio (VITRO) score predicts hepatic decompensation and mortality in cirrhosis [12] 

In this retrospective analysis, compensated cirrhotics were recruited and followed for a median of 45 months. The purpose was to determine if the ratio of von Willebrand Factor antigen to platelets, called the VITRO score, could be used to predict decompensation and mortality. In patients with a VITRO score ≥2.5, the risk of decompensation after 1 year was 9% (95% CI, 3-16%) vs. 0% (95% CI, 0-0%) when compared to a score <2.5; similar findings were seen after 2 years. VITRO seems to be a valuable prognostic tool, and would benefit from being studied on a larger scale.

International evaluation of an AI system for breast cancer screening [13] 

This study evaluated a new artificial intelligence (AI) system for breast cancer prediction. It compared AI against radiologists in clinical practice in the UK and US by using biopsy-confirmed breast cancer as the outcome. The AI system showed statistically significant improved specificity in both the UK and US datasets. Sensitivity was non-inferior in the UK dataset, but AI had greater sensitivity in the US dataset. AI may serve to decrease recall rates and unnecessary biopsies, and potentially improve our ability to flag suspicious findings.

Dr. Brandon Adelson is a first-year resident in internal medicine at NYU Langone Health

Peer reviewed by Christian Torres, MD, chief resident, internal medicine, NYU School of Medicine

Image courtesy of Pixabay


[1] Conaghan PG, Bowes MA, Kingsbury SR, et al. Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized, Placebo-Controlled Study. Ann Intern Med. 2019; [Epub ahead of print 31 December 2019]

[2] Vos T,  Flaxman AD,  Naghavi M,  et al Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet2012380216396

[3] Karsdal MA,  Bay-Jensen AC,  Lories RJ,  et al. The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis20147333648

[4] Yao P, Bennett D, Mafham M, et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(12):e1917789.

[5] Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367(9527):2010-2018.

[6] Watts NB, Manson JE. Osteoporosis and fracture risk evaluation and management: shared decision making in clinical practice. JAMA. 2017;317(3):253-254

[7] Woolen SA, Shankar PR, Gagnier JJ, MacEachern MP, Singer L, Davenport MS. Risk of Nephrogenic Systemic Fibrosis in Patients With Stage 4 or 5 Chronic Kidney Disease Receiving a Group II Gadolinium-Based Contrast Agent: A Systematic Review and Meta-analysis. JAMA Intern Med. Published online December 09, 2019.

[8] Mendoza  FA, Artlett  CM, Sandorfi  N, Latinis  K, Piera-Velazquez  S, Jimenez  SA.  Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.  Semin Arthritis Rheum. 2006;35(4):238-249

[9] Altun  E, Martin  DR, Wertman  R, Lugo-Somolinos  A, Fuller  ER  III, Semelka  RC.  Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy—report from two US universities.  Radiology. 2009;253(3):689-696.

[10] ACR Committee on Drugs and Contrast Media. ACR manual on contrast media, version 10.3. Published June 2018.

[11] Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar lavage fluid associated with EVALI. N Engl JMed 2019.

[12] Schwarzer, R., Reiberger, T., Mandorfer, M. et al. The von Willebrand Factor antigen to platelet ratio (VITRO) score predicts hepatic decompensation and mortality in cirrhosis. J Gastroenterol (2019)

[13] McKinney, S.M., Sieniek, M., Godbole, V. et al. International evaluation of an AI system for breast cancer screening. Nature 577, 89–94 (2020)