Tag Archives: bone

Cool Discovery: Bones Have Lymphatics!

The lymphatic system is a network of vessels that helps regulate fluid homeostasis, waste clearance, and immune response. Most tissues in the body have some type of lymphatic drainage. The main holdouts have been the brain, the eyes, and our bones.

Ten years ago, the brain lymphatic system (called glymphatics since they are associated with neuroglial cells) was discovered. This system is critically important to brain health. During deep sleep, our neurons shrink in size, allowing CSF to flush through the glymphatic system. This sweeps the accumulated debris (including tau and beta-amyloid) out through the glymphatics to be disposed of.

In 2014, Schlemm’s canals in the eye were also identified as functioning as a lymphatic system. These collect the aqueous humor absorbed by the trabecular meshwork on the surface of the iris.

And now, the Institute of Molecular Medicine at Oxford has discovered a lymphatic network in our bones! As anybody who has played with a microscope can attest, it’s easy and fascinating to view soft tissues. But working with calcified tissue is very challenging. For this reason, the organization of blood vessels in bone has been difficult to observe.

The authors used light sheet fluorescence microscopy to image intact bone specimens. This technique shines a sheet of laser light through a labeled specimen. A fluorescence detector perpendicular to the sheet of light records light output from the tagged items of interest in one two-dimensional layer. This technique can actually be used in living specimens, although in this study the bones were prepped and the calcium was carefully removed.

The authors identified lymphatics in mouse and human bone specimens. They also found that these lymphatics expanded in response to stress, which resulted in formation of more lymphatics. This, in turn, induced regeneration of the bone itself and hemopoietic cells in the bone marrow. However, as the animals aged, their lymphangiogenesis lessened, which may explain why bones in the elderly do not heal as well or as quickly.

Bottom line: This is an exciting discovery using a novel imaging technique. It showed not only the structure of these lymphatics but also their role in healing from injury. It raises the interesting possibility that manipulating the lymphatic endothelial cells might allow us to accelerate healing after injury.

First, we had lymphatics. Then, when they were found in the brain, we called them “glymphatics.” So now I will take the prerogative to name the ones discovered in bone as “blymphatics.” Not very sexy, but you get the idea!

Reference: Lymphatic vessels in bone support regeneration after injury. Cell. 2023 Jan 19;186(2):382-397.e24. doi: 10.1016/j.cell.2022.12.031. PMID: 36669473.

The Impact Of NSAIDs On Fracture Healing

In my last post I discussed some of the basic effects of NSAIDs on bone healing. Now let’s see if theory applies to practice.

In 2003, several papers brought to light possible interactions between these drugs and fracture healing. Specifically, there were questions about these drugs interfering with the healing process and of increasing the number of delayed unions or nonunions. But once again, how convincing were these papers, really?

It would seem to make sense that NSAIDs could interfere with bone healing. The healing process relies heavily on the regulation of osteoblast and osteoclast function, which itself is regulated by prostaglandins. Since prostaglandins are synthesized by the COX enzymes, COX inhibitors like the NSAIDs should have the potential to impair this process. Indeed, animal studies in rats and rabbits seem to bear this out.

But as we have seen before, good animal studies don’t always translate well into human experience. Although a study from 2005 suggested that NSAID administration in older patients within 90 days of injury had a higher incidence of fracture nonunion, the study design was not a very good one. It was equally likely that patients who required these drugs in this age group may have been at higher risk for nonunion in the first place.

A meta-analysis of human studies was performed in 2011. Out of 558 potential studies, only 5 met criteria review. (This is yet another reminder of the sheer amount of sub-par research out there.) The authors found that short-term use (< 14 days) of normal dose NSAIDS was not associated with non-union. High doses of ketorolac (> 120mg/day) and diclofenac sodium (> 300mg total) did have an association. But remember, this does not show causation. There are many other factors that can impede healing (smoking, diabetes, etc).

A study from 2016 examined the effect of ketorolac administration on fracture healing in patients undergoing repairs of femoral and tibial fractures. It did not find an association between non-union and ketorolac, but did find one with smoking. Unfortunately, the study was small (85 patients given ketorolac, 243 controls without it). It probably does not have the statistical power to detect any difference with the NSAID. A power analysis was not provided in the methods section.

Bottom line: Once again, the animal data is clear and the human data less so. Although there are theoretical concerns about NSAID use and fracture healing, there is still not enough solid risk:benefit information to abandon short-term NSAID use in patients who really need them. NSAIDs can and should be prescribed in patients with short-term needs and simple fractures, and consider COX-1 specific drugs like ketorolac while your patient is in the hospital. And we do have some evidence that high-dose NSAIDs may have some impact, so stick to the usual doses for just as long as they are needed for pain management.

References:

  1. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J AM Acad Orthop Surg 12:139-43, 2004.
  2. Effect of COX-2 on fracture-healing in the rat femur. J Bone Joint Surg Am 86:116-123, 2004.
  3. Effects of perioperative anti-inflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy 25:1566-1591, 2005.
  4. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury 39:384-394, 2008.
  5. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth 52:506-512, 2005.
  6. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev 4(3), 2016.
  7. High-dose ketorolac affects adult spinal fusion. Spine 36(7):E461-E468, 2011.
  8. Ketorolac administered in the recovery room for acute pain management does not affect healing rates of femoral and tibial fractures. J Orthop Trauma 30(9):479-482, 2016.

NSAIDs And Bone Healing: How Do They Impact It?

The arguments about whether NSAID administration has any effect on bone healing continues to be argued by our orthopedic and spine surgery colleagues. In the early days of research in this area (about 20 years ago) there were concerns in animal models that there might be a problem. Apparently lots of rats and bunnies were suffering from fractures in those days.

But physiologically, how could NSAIDS do this? Here’s a simplified diagram of how the bone healing process works.

First, an acute injury occurs and macrophages and other cells move into the area to start the inflammatory process. COX-2 receptors are highly expressed on these cells, resulting in an increase in prostaglandin E2 (PGE2) production.

PGE2 then promotes proliferation of stem cells that differentiate into osteoblasts, which in turn begin forming bone to repair the injury.  In theory, if PGE2 is reduced in the healing area there is the possibility that bone formation may be impaired, leading to non- or malunion or refracturing.

Administration of NSAIDs can block COX-1 and COX-2 receptors throughout the body. This serves to decrease prostaglandin production and hence reduces inflammation and pain. Doesn’t it follow that giving these drugs should be bad for bone formation in patients with fractures?

Not so fast! There are a number problems with this argument. First, not all NSAIDs are created alike. Here is a chart that shows where the primary focus of COX inhibition is with some common NSAIDs.

Note how the common over-the-counter drugs affect both COX-1 and COX-2, yet there are some that are more selective. So the choice of drug may be relevant.

And we can’t assume that an in vitro effect in a Petri dish of cells actually carries over into the in vivo world. Many researchers rely initially on animal models to study drug effects in vivo. Predictions based on studies of rats and bunnies frequently do not pan out in humans.

We are left with only a theory based on an understanding of the basic mechanism of bone healing. Tune in to my next post where I discuss the research that’s been done in this field and whether it actually translates into human bone healing or not.

Salmon Calcitonin After Spine Fractures?

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.