Prophylaxis of heterotopic ossification – an updated review.

Baird EO and Kang QK. Journal of orthopaedic surgery and research. 2009; 4: 12. The full text is available online as an 'open access' article.

This is the editor's interpretation of a paper published in the orthopaedic literature in 2009 - our attempt to make relevant medical articles accessible to lay readers. If you wish to read the original it is easy to ask your librarian to obtain a reprint for you from any medical library.


This is a review paper, where the authors have combed the medical literature from 1958 to 2008 looking at the issue of 'prophylaxis' [prevention] of 'heterotopic ossification' (HO) [the formation of bone in soft tissue where it does not normally exist].

The authors point out that HO can form in muscles, ligaments and tendons, after trauma, surgery, nerve tissue injury or burns, but it is most commonly seen in the hip either after fracture of the hip with ORIF (open reduction and internal fixation) [with metal put into the bone to fix the fracture] or after hip replacement surgery.

The incidence of HO after total hip replacement varies in different publications from 5% to 90%, but the important point is that only 3% to 7% have significant symptoms. In total knee replacement their investigations have identified that the reported incidence is lower (3.8% to 39%) but with only 1% being significantly symptomatic.

Mechanisms of heterotopic ossification

The authors divide the initiating mechanism to fall into one of three groups -

  • neurological (eg after head injury or spinal cord injury)
  • genetic
  • traumatic (eg after injury or surgery. Most orthopaedic HO falls into this group)

but there is still wide debate about actually how the whole abnormal process sets itself off.

Several different factors seem to have the potential to trigger normal 'pluripotential' cells [cells that are able to change their function] to abnormally turn into cells that can form bone -

  • prostaglandin activity [a group of substances that can affect a wide variety of cellular processes within the body]
  • hypercalcaemia [increased calcium levels in the bloodstream]
  • tissue hypoxia [reduced oxygen supply to the tissues, usually via the bloodstream]
  • alterations in sympathetic nerve activity [the part of the nervous system that controls the body's internal organs]
  • prolonged immobilisation [eg after spinal cord injury]
  • imbalances between parathyroid hormone activity and calcitonin [the hormonal calcium control system in the blood]

In addition to these factors, the authors identify other factors that further increase the risk of HO being triggered -

  • having HO previously on the opposite limb [eg a second hip replacement but on the other side]
  • hypertrophic osteoarthritis following injury [arthritis triggered by an injury and in which the bony destruction is accompanied by bony overgrowth in other areas]
  • rheumatoid arthritis [a severe form of arthritis in multiple joints, accompanied by immune system problems]
  • ankylosing spondylitis [a fusing-up of the vertebral bones]
  • diffuse idiopathic skeletal hyperostosis [widespread bony overgrowths of unknown cause]
  • Paget's disease [a disorder of bony re-modelling where the bone areas are abnormal, enlarged and brittle]
  • the male sex

Prevention of HO

NSAIDs(non-steroidal anti-inflammatory drugs)

The drug indomethacin (one of the NSAID group) has been proven to help prevent HO. It is also very cheap. Literature research by the authors led them to state that "for every 100,000 THAs [total hip replacements] performed in the US each year, perioperative [ie around the time of surgery] NSAID use has the potential to prevent anywhere from 10 to 20,000 cases" of HO. They note specifically that aspirin does not seem to have the same effect.

A problem with indomethacin, they point out, is that in some patients the drug upsets their tummies (sometimes as bad as causing stomach ulcers) and some patients cannot manage to tolerate it. Also the drug may lead to the wound bleeding more than usual as it affects the blood clotting mechanism. So other NSAIDs are being tried, such as meloxicam, but high dose indomethacin nonetheless remains the 'gold standard'.

One other problem with NSAIDs according to the authors is that their very action in inhibiting HO also means that they inhibit normal bony healing, so that bony fractures take longer to unite or may fail to unite at all. Ligaments may also be slower to heal. There is also a risk in the joint replacement patients of the prosthesis becoming loose.

Radiation therapy

As early as 1958 papers were published that demonstrated that irradiation inhibited bone repair. The early workers found that this inhibiting effect was greatest closer to the time of fracture, and deduced that the radiation was affecting the progenitor cells [the undifferentiated type of cell, like a stem cell, that has the potential to develop into other cell types], ie the kind of cells that are part of the abnormal HO process.

The authors point out that nowadays irradiation is relatively commonly used to prevent HO pre- and post-operatively in high risk situations, and particularly in patients with a previous history of HO but are undergoing further surgery. They point to literature that demonstrates irradiation to be highly efficacious, and note that it does not make any difference whether it is used pre-operatively or post-operatively - both are equally effective.

With regards to the risks associated with irradiation, although theoretically radiation-induced cancer is a risk, it seems that the low doses used and also the fact that most patients are in the older age group (and therefore there is not the time for cancer to establish) diminishes the real risk to negligible levels. However, irradiation has another problem, like with the indomethacin discussed above, in that normal bone healing is also affected. In the hip, according to the authors, this can be a problem in revision surgery [re-doing a hip replacement] when an osteotomy [cutting the bone] needs to be done to remove the old prosthesis and the irradiation inhibits the osteotomy site from healing again. Another problem in hip surgery is that the testicles can be affected by the irradiation, dropping the sperm count, and for both these two problems shielding has been advocated to minimise the problems.

Other

These two treatments form the mainstay of prevention of HO, but because of the problems that the authors have pointed out with both indomethacin and irradiation, there are other options being explored -

  • Noggin - This is a substance that normally plays a role in the pathways of bone development. At the date when this article was published its use was confined to animal experiments, but it seems very effective and also it can be delivered very finely to the site of the problem by piggy-backing it onto certain viruses.
  • Pulsed Electromagnetic Fields (PEMF) - This seems to work by increasing blood flow and oxygen to the involved tissues.
  • Free Radical Scavengers - The explanation given by the authors is quite complicated but it appears that both spasm and also immobilisation of muscles can cause the release of free radicals, and these can reduce oxygen to the tissues and trigger the HO.  Allopurinol and N-acetylcysteine (A/A) are two drugs that act as free radical scavengers and they seem to be very promising options in the prevention of HO.

The authors point out that these last three are still in an early stage of research but that they look promising and may offer better prophylaxis with fewer side effects than NSAIDs or irradiation.

 

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