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Evaluating

the

role

of

calcium

sulphate

in

the

treatment of

chronic osteomyelitis

1. Chronic osteomyelitis overview

Jack Carruthers

4. What are the options?

Aetiology PMMA beads Haematogenous seeding (rare in West); post-traumatic (especially in compound fractures); infected foreign body.
Aetiology
PMMA beads
Haematogenous seeding (rare in West); post-traumatic (especially in compound
fractures); infected foreign body.
Pathology
Bacterial entry into bone triggers an acute inflammatory response. Bacterial
virulence factors disrupt the blood supply, leading to the formation of a necrotic
sequestrum. The infection progresses to chronicity due to damaged skin,
abundant scarring, and impaired vascularity. Patient factors including
malnutrition, diabetes mellitus and smoking contribute to infection persistence.
Infection can spread to the soft tissues causing a discharging sinus.
These were developed by Klemm in the 1970s (4). The delivery of antibiotics by
PMMA bead chains to the osteomyelitic cavity was demonstrated to be
in the order of 200 times that of systemic antibiotics (5). In rabbit
experimental models, treatment of osteomyelitis with PMMA beads
showed a 100% success rate at preventing infection recurrence (6).
Human studies by Nelson et al. demonstrated a reduction in the risk of
infection recurrence of 18% in patients treated with PMMA beads versus
conventional therapy (7). PMMA seemed to be the way forward; but a
major concern is that they require a second operation to remove.
Therefore, the focus is now on resorbable antibiotic carriers.
Clinical features
Collagen fleece
Localised bone pain accompanied by erythema, and swelling. Sometimes there
are symptoms of systemic infection. A raised ESR and CRP can be present.
Diagnosis
Although widely used and biodegradable, collagen fleece has numerous draw-
backs. It is associated with seroma formation, and a recent study
demonstrated that it eluted 95% of its gentamicin in the first day (8).
Radiological features include: loss of trabecular architecture, osteopaenia,
scalloping of the inner surface of the bone cortex, periosteal involucrum
formation seen next to a radio-dense sequestrum. (1)
5. Calcium sulphate
2. Current treatment rationale
Chronic osteomyelitis is primarily a surgical disease (2):
The first documented use of calcium sulphate, a
bioceramic, to treat bone infections was in 1842 by
Dreesmann (2). Since then, it has been loaded with
antibiotics to create a superior bone graft substitute
and is capable of effective dead-space management:
•Debride the area of osteomyelitis.
•Take no less than 5 microbiology samples for culture and sensitivity, and 3-5
histology samples.
•Excise the area of necrotic bone, aiming for healthy bleeding bone at the cut
margins.
•Dead-space management of the cavity, including antibiotic-loaded carriers.
•Optional muscle flaps can promote revascularisation and healthy bone
formation, and provide soft-tissue coverage of the bone compartment.
•Growth of new bone to fill the cavity can be encouraged by bone grafting and
osteoconductive bone graft substitutes.
Antibiotic characteristics
Elution kinetics of many antibiotics, including
gentamicin, were investigated by Wichelhaus et al.
Calcium sulphate releases antibiotic over 10 days or
more in amounts well above the MIC of most
bacteria (9). It provides high local antibiotic
concentrations without systemic side-effects (10).
Resorbable
Fig. 2. View of calcium
sulphate beads on plain X-
ray before resorption (10).
A prospective study into calcium sulphate pellet
treatment showed full resorption by 6 months post-
treatment (10). This obviates the need for a second
operation to remove the dead-space filler.
Fig. 1. View of calcium sulphate
beads being introduced into a
debrided and excised cavity
(adapted from (13)).
Osteoconductivity
3. Antibiotic-loaded carriers
What? Usually of an inert substance, they are loaded with broad-spectrum
antibiotics and placed into the excision cavity.
Why? They deliver high concentrations of antibiotics locally without the side-
effects of high-dose systemic antibiotics. In addition, they are important
in dead-space management, preventing haematoma formation. The
osteoconductive carriers act as bone graft substitutes, helping new bone
grow to fill the cavity (3).
Immunofluorescence studies demonstrated that both
osteoblasts and osteoclasts could adhere to a
calcium sulphate scaffold (11). Chang showed that
patients achieved full weight bearing status 3
months post-treatment for chronic osteomyelitis,
suggesting sufficient bone in-growth (12). Recently,
Franceschini et al. used X-rays 12 months post-op to
show that calcium sulphate Herafill beads, used at
the NOC, provide support for undisturbed re-
ossification of the tibia, proving it to be an effective
bone graft substitute (13).
Infection control
In goat-models of tibial chronic osteomyelitis,
tobramycin-impregnated calcium sulphate beads
loaded into the dead-space prevented recurrence of

6. Are there other suitable bioceramics?

Evaluating the role of calcium sulphate in the treatment of chronic osteomyelitis 1. Chronic osteomyelitis overview

Current research into bioceramics including calcium sulphate have aimed to optimise their osteoconductivity. Options other than calcium sulphate include tricalcium phosphate (TCP) and silicated calcium phosphate (Si-CaP). A comparative study by Hing et al. showed that calcium sulphate is resorbed too quickly to provide a smooth continuum between resorption and adsorption of bone. Indeed, the osteoconductive kinetics of Si-CaP were superior, demonstrating re-vascularisation and bone apposition over 3-6 weeks (17).

7. Caveats to calcium sulphate use

The limits of osteoconductivity?

The osteoconductivity of calcium sulphate has been called into question in a number of studies, not least Hing et al. Stubbs showed that while calcium sulphate provided support for some bone in-growth, it did not result in complete filling of the defect before total resorption (18). Moreover, the pattern of bone in-growth in calcium sulphate is sporadic rather than gradual.

Inflammation?

High rates of resorption may result in microparticle-induced inflammation. The resulting acidic environment favours osteoclast action and further degradation of the ceramic (19). However, numerous studies challenge this contention, and anecdotally, the NOC has not encountered this problem.

8. Conclusions: the future

Calcium sulphate fulfils the primary goal for the treatment of any disease:

patient satisfaction. Ultimately, it is a tool which allows patients to achieve an infection-free fully functional bone or joint.

Calcium sulphate can only be improved. Recent experiments have combined calcium sulphate with hydroxyapatite (HA) to improve biocompatibility and osteoconductivity. Both Stubbs et al. and Rauschmann et al. highlighted superior bone graft properties in calcium sulphate-HA composite carriers (18, 20). Adding a silicon component could enhance its ability to stimulate bone metabolism (17).Combining calcium sulphate with mesenchymal stem cells to promote new bone formation and stem cell osteogenic differentiation may be the next step (21).

9. References

(1)

Berendt, A., ‘Chapter 41: Acute and chronic osteomyelitis’, In Cohen, J. et al., Infectious Diseases, volume one, Mosby Elsevier, p.p. 445-456.

(2)

Parsons, B. and E. Strauss, Surgical management of chronic osteomyelitis, The American Journal of Surgery, 188, 57S-66S (2004).

(3)

El-husseiny, M. et al., Biodegradable antibiotic delivery systems, The Journal of Bone and Joint Surgery, 93-B, 151-157 (2011).

(4)

Klemm, K. W., Gentamicin-PMMA chains (Septopal chains) for the local antibiotic treatment of chronic osteomyelitis, Reconstructive Surgery and Traumatology, 20, 11-35 (1988).

(5)

Wahlig, H. et al., The release of gentamicin from PMMA beads: an experimental and pharmacokinetic study, The Journal of Bone and Joint Surgery, 60-B, 270 (1978).

(6)

Evans, R. P. and C. L. Nelson, Gentamicin-impregnated PMMA beads compared with systemic antibiotic therapy in the treatment of chronic osteomyelitis, Clinical Orthopaedics and Related Research, 295,

(7)

37-42 (1993). Nelson, C. L. et al., A comparison of gentamicin-impregnated polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected total hip and knee arthroplasty, Clinical

(8)

Orthopaedics and Related Research, 295, 96-101 (1993). Sørensen, T. S., et al., Rapid release of gentamicin from collagen sponge: in vitro comparison with plastic beads, Acta Orthopaedica Scandinavica, 61, 353-361 (1990).

(9)

Wichelhaus, T. A. et al., Elution characteristics of vancomycin, teicoplanin, gentamicin and clindamycin from calcium sulphate beads, Journal of Antimicrobial Chemotherapy, 48, 117-119 (2001).

(10)

McKee, L. et al., The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: early results of a prospective trial, Journal of Orthopaedic

(11)

Trauma, 16, 622-627 (2002). Sidqui, M. et al., Osteoblast adherence and resorption activity of isolated osteoclasts on calcium sulphate hemihydrate, Biomaterials, 16, 1327-1332 (1995).

(12)

Chang, W. et al., Adult osteomyelitis: debridement versus debridement plus Osteoset T® pellets, Acta Orthopaedica Belgica, 73, 238-243 (2007).

(13)

Franceschini, M. et al., Treatment of a chronic recurrent fistulised tibial osteomyelitis: administration of a novel antibiotic-loaded bone substitute combined with a pedicular muscle flap sealing, European

(14)

Journal of Orthopaedic Surgery and Traumatology, Published online (2012). Thomas, D. B. et al., Tobramycin-impregnated calcium sulphate prevents infection in contaminated wounds, Clinical Orthopaedics and Related Research, 441, 366-371 (2005).

(15)

Nelson, C. L. et al., The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets, Journal of Orthopaedic Research, 20, 643-647 (2002).

(16)

Bouillet, R. et al., Traitement de l’osteomyélite chronique en milieu africain par implants de plâtre impregne d’antibiotiques, Acta Orthopaedica Belgica, 55, 2-11 (1989).

(17)

Hing, K. A. et al., Comparative performance of three ceramic bone graft substitutes, The Spine Journal, 7, 475-490 (2007).

(18)

Stubbs, D. et al., In vivo evaluation of resorbable bone graft substitutes in a rabbit tibial defect model, Biomaterials, 25, 5037-5044 (2004).

(19)

Lu, J. et al., Relationship between bioceramics sintering and micro-particles-induced cellular damages, Journal of Materials Science: Materials in Medicine, 15, 361-365 (2004).

(20)

Rauschmann, M. A. et al., Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections, Biomaterials, 26, 2677-2684

(2005).

(21)

Ueng, S. W. et al., Biodegradable alginate antibiotic beads, Clinical Orthopaedics and Related Research, 380, 250-259 (2000).