Category Archives: Complications

Salmon Calcitonin After Spine Fractures?

November 22, 2021 The Trauma Pro Leave a comment

In my last post, I reviewed some data on the effectiveness of starting Vitamin D supplements after a patient sustains a fracture. The idea was that they might start building better bone and heal their fractures more readily if they boost their D levels. Unfortunately, this was not shown to be true.

Vitamin D improves bone health by facilitating absorption of calcium from the gut. This is a bit indirect and relies on sufficient intake of calcium and good hormonal regulation that directs osteoblasts to incorporate the mineral into bone. Why not work with those hormones directly to try to increase the amount of calcium that is deposited?

Calcitonin is a peptide hormone that has two major effects on calcium levels: it inhibits osteoclast activity that is breaking down bone and releasing calcium from it, and it inhibits calcium reabsorption in the kidneys which causes more to be excreted in the urine.

Perhaps giving calcitonin after sustaining a fracture might improve healing. Many orthopedic surgeons and neurosurgeons swear by this drug. Unfortunately, there are very few randomized, controlled studies of its use for this indication. A meta-analysis was performed that examined both utility and cost-effectiveness that I found interesting.

Here are the factoids:

There was some mild evidence that nasal calcitonin was effective in preventing vertebral fractures
- One paper showed a benefit when giving 200 IU of intranasal salmon calcitonin daily over a 5 year period
- But a benefit was not shown if 100 or 400 IU were given (this is weird)
- A marker of bone turnover showed equal reduction in 200 and 400 IU groups (why isn’t this less in the 200 IU group?)
Financial analysis showed that it was only marginally cost effective
Current retail pricing is about $125 for a month supply
Mild side effects like runny nose and nausea are common
Intranasal calcitonin has been shown to reduce pain during healing of vertebral fractures

Bottom line: What does all of this mean? First, salmon calcitonin might decrease the number of future vertebral fractures. I say might because only the 200 IU dose in the study showed this effect. I can see where higher doses might be more effective to a point, but having only the middle dose show up as effective is just odd and makes me worry about the study.

The data does seem compelling that taking this product decreases pain during fracture healing. A meta-analysis of this showed that the effect probably only lasts up to a month.

And finally, from a cost-effectiveness standpoint for avoiding future fractures, this medication is marginal. Luckily, it is relatively cheap at $125 retail and about $25 with insurance in the US.

Wrapping it all up, intranasal salmon calcitonin might reduce fracture pain for a month and might decrease the likelihood of future vertebral fractures. However, the data are weak enough that cost-effectiveness is borderline. And there are more effective (and cheaper) analgesics available.

The absolute best way to strengthen bones is to exercise, especially engaging in weight-bearing activities. Not only does this strengthen bones, it also increases overall fitness and health. In general, medications are not the way to go to strengthen bones. It took decades for your patient to become osteoporotic. And while these drugs might improve their bone density slowly, a graduated and supervised exercise regimen is probably the best thing you can do for them.

References:

Efficacy of calcitonin for treating acute pain associated with osteoporotic vertebral compression fracture: an updated systematic review. CJEM 2020 May;22(3):359-367.
A Randomized Trial of Nasal Spray Salmon Calcitonin in Postmenopausal Women with Established Osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. PharmacoEconomics, 2001, Vol.19 (5), p.565-575.
A randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy and safety of oral salmon calcitonin in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D. Bone 2016 Oct;91:122-9.

Complications, Extremity

Giving Vitamin D After Fracture: Helpful Or Not?

November 16, 2021 The Trauma Pro Leave a comment

The role of Vitamin D in fracture healing is well known. So, of course, trauma professionals have tried to promote Vitamin D supplementation to counteract the effects of osteoporosis. A meta-analysis of of 12 papers on the topic relating to hip and other non-vertebral fractures showed that there was roughly a 25% risk reduction for any non-vertebral fractures in patients taking 700-800 U of Vitamin D supplements daily.

Sounds good, right? So what about taking Vitamin D after a fracture occurs? Seems like it should promote healing, right? A large meta-analysis in an orthopedics journal looked at this very question.

Unfortunately, there was a tremendous variability in the interventions, outcomes, and measures of variance. All the authors could do was summarize individual papers, and a true meta-analysis could not be performed.

Here are the factoids:

81 papers made the cut for final review
A whopping 70% of the population with fractures had low Vitamin D levels
Vitamin D supplementation in hospital and after discharge did increase serum levels
Only one study, a meeting abstract which has still not seen the light of day in a journal, suggested a trend toward less malunions following a single loading dose of Vitamin D

Bottom line: Vitamin D is a great idea for people who are known to have, or are at risk for, osteoporosis and fractures. It definitely toughens up the bones and lowers the risk of fracture. However, the utility of giving it after a fall has not been shown. Of the 81 papers reviewed, none showed a significant impact on fracture healing. The only good thing is that Vitamin D supplements are cheap. Giving them may make us think that we are helping our patient heal, but it’s not.

What about the use of calcitonin for preventing future fractures? Find that in my next post!

References:

What is the role of vitamin D supplementation in acute fracture patients? A systematic review and meta-analysis of the prevalence of hypovitaminosis D and supplementation efficacy. J Orthopaedic Trauma 2016 Feb;30(2):53-63.
Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 293(18):2257-2264, 2005.

Complications

TXA, Thromboembolic Events, And Mortality

October 4, 2021 The Trauma Pro Leave a comment

I’ve visited several hundred trauma centers over the past 25 years, and recently I’ve begun to appreciate that there are two camps when it comes to the use of tranexamic acid: the TXA believers and the TXA hesitant.

There have been a number of large studies that seem to suggest a benefit with respect to survival from major hemorrhage, particularly if given soon after injury (CRASH-2, MATTERs). This drug is dirt cheap and has been around a long time, so it has a clearly defined risk profile.

However, many of those hesitant to use it point to the possibility of thromboembolic events that have been sporadically reported. Several years ago, I did my own literature review and found that the number of thrombotic events from TXA was nearly identical to that of transfusing plasma.

JAMA Surgery just published a large systematic review, meta-analysis, and meta-regression that sought to examine the association between thromboembolic events (TE) in patients of any age and involving all medical disciplines, not just trauma.

The anesthesia group at the University Hospital Frankfurt in German did a systematic search of the Cochrane Central Register of Controlled Trials, as well as MEDLINE, for randomized controlled trials involving TXA. They covered all published studies through December 2020.

The authors adhered to standard guidelines for conducting reviews and meta-analysis (PRISMA). They specifically searched for outcomes involving TEs, such as venous thromboembolism, myocardial infarction or ischemia, limb ischemia, mesenteric thrombosis, and hepatic artery thrombosis. They also tallied the overall mortality, bleeding mortality, and non-bleeding mortality.

Here are the factoids:

A total of 216 eligible trials were identified that included over 125,000 patients (!)
Total TEs in the TXA group were 1,020 (2.1%) vs 900 (2.0%) in the control group
Studies at lowest risk for selection bias showed similar results

Bottom line: The authors concluded that IV TXA, irrespective of the dose, does not increase the risk of thromboembolic events. Period.

Hopefully, this is the final study needed to convince the TXA hesitant that it is safe to administer. They may still argue the efficacy, but at less than $100 per vial it is becoming impossible to ignore.

Reference: Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery 156(6):3210884, 2021.

Abstracts, Complications

Best Of AAST 2021: Comparing Two Different Doses Of Enoxaparin

September 22, 2021 The Trauma Pro Leave a comment

Oh, look, my favorite topic! Prevention of venous thromboembolism (VTE) and complications. We’ve grown accustomed to using enoxaparin at the standard 30mg bid dose for a long time. The orthopedic surgeons like to use 40mg qd, and there is some literature that shows this is reasonable for fracture patients.

The group at OHSU in Portland wanted to show that the single dose regimen is just as safe and effective as the bid dose. They performed a seven year, prospective, randomized trial of the two dose regimens. Weekly screening duplex exams were performed. The outcome measured was the occurrence of deep venous thrombosis (DVT) in the legs. They also examined missed doses, bleeding complications, and hospital length of stay.

Here are the factoids:

There were 267 total patients, 139 on the single dose regimen and 128 in the bid group
Average age was 49 and BMI was 28 in both groups
DVT occurred in 15 (11%) qd patients and 12 (9%) bid patients
Bleeding occurred in 19% of qd patients vs 14% of bid patients
There were fewer missed doses in the qd patients
None of the differences were statistically significant

The authors concluded that the qd dose was similar to the bid dose and is equally efficacious.

Bottom line: Hold on, now. First, this is a non-inferiority study. Daily dosing is presumed to be as good as twice daily dosing since there was no statistical difference seen between groups. This assumes that you have the statistical power (enough patients) to detect a difference. Is this the case here?

I pulled out my Sample Size calculator to check this over. I work things backwards to see the magnitude of difference that would have to be present for the given number of subjects. It looks like a sample size this small would only be able to detect a difference of 2x in the DVT occurrence result!

Lets look at this in simple terms. The absolute number of DVTs was actually higher in the qd group (11% vs 9%). So let’s say it is actually inferior to bid, meaning that the higher occurrence of DVT is real. Using the number of subjects here, the incidence could rise to 20% in the qd group and still not reach significance.

The other major issue is the potential for selection bias. This study took place over 7 years. Yet only 267 were enrolled, or 38 patients per year. But this trauma center admits several thousand patients annually. If the enrollment criteria were so strict, the subjects probably don’t represent the general population. And if they weren’t, where did all the patients go? This is most likely a skewed study group.

I have lots of questions for the presenter and authors on this one!

Please show us your power calculations. Are you sure you have the statistical oomph to show non-inferiority?
Why did it take so long to accumulate 267 subjects? Show us the statistics for your overall trauma population to make sure they look the same.
Were you able to detect any other complications like pulmonary embolism?

Lots of questions here! Hopefully there’s much more information in the presentation!

Reference: A PROSPECTIVE RANDOMIZED TRIAL COMPARING TWO
STANDARD DOSES OF ENOXAPARIN FOR PREVENTION OF
THROMBOEMBOLISM IN TRAUMA. AAST 2021, Oral abstract 40.

Abstracts, Complications

Best Of AAST: Delayed Treatment Of Blunt Carotid And Vertebral Injury

September 15, 2021 The Trauma Pro Leave a comment

I recently published a series on blunt carotid and vertebral artery injury (BCVI). Today, I’ll review an AAST abstract that details the results of a multicenter study on the timing of medical treatment of this condition. This typically takes the form of anti-platelet agents, usually aspirin.

The trial collected prospective, observational data from 16 trauma centers. Patients had to receive medical therapy at some time after their injury or they were excluded. The stroke consequences of early vs late medical therapy were evaluated, where late was defined at > 24 hours.

Here are the factoids:

There were 636 BCVI included in the study
Median time to first medical therapy was 11 hours in the early group and 62 hours in the late group
ISS was higher in the delayed group (26 vs 22); although this was “statistically significant”, it is probably not a clinically significant difference
There was no increase in stroke rate with later administration of medical treatment

Bottom line: This is a very interesting study. We always worry about missing BCVI (see my previous post here), and now we know a little more about what happens if we do. The authors suggest that the stroke rate does not go up if medical management is delayed, say for some other potential bleeding issue.

This is a reasonably large data set, but the key thing to consider is the time frame observed. The median delay to medical management was only about 2.5 days. Were there any strokes involved in the patients with much longer delays? That is the real question. And were there any strokes that occurred despite early/immediate medical management?

The descriptive statistics and simple analyses presented do not provide all of the information we need. A stoke is a very significant adverse event for the patient. Statistical means are fine, but information on the specific patients who suffered one is necessary to truly understand this issue.

Here is my question for the presenter and authors:

Please break down the details on all patients who suffered a stroke. It will be very interesting to see if there were any in the early group and if there was a trend toward stroke in the very late tail data.

Reference: DOES TREATMENT DELAY FOR BLUNT CEREBROVASCULAR INJURY AFFECT STROKE RATE?: AN EAST MULTICENTERTRIAL. AAST 2021, Oral abstract #23.

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