Can new technological advances facilitate a more accurate diagnosis of osteomyelitis and more successful treatment? These authors consider this question and offer insights from the literature on lab tests, imaging modalities and effective treatments with an eye toward prevention.
Diabetes prevalence is at an all time high and current estimates show that 200 million individuals have the disease worldwide. This number is expected to grow to over 300 million over the next 10 years.1 Even though patients with diabetes are not the only patient population plagued by osteomyelitis, they are certainly at the top of the list when we consider those most at risk for this complication.
New and emerging developments are happening in the areas of laboratory testing, radiographic imaging and antibiotic bead preparations. The single most important development in the treatment of osteomyelitis, however, may be a new focus toward early diagnosis and prevention, particularly in those at risk for diabetic neuropathy.
Patients acquire acute osteomyelitis through a number of different mechanisms. Hematogenous methods of bacterial seeding are present in a bimodal distribution that occurs in both the very young and elderly populations. A small defect in the bone with a simultaneous or prior remote infection can result in seeding of the highly vascular and tortuous metaphyseal areas of bone. This means of acquiring osteomyelitis is rare in adult populations and most commonly happens in children.2
Direct or contiguous extension involves the penetration of bone by means of a sharp object or surgical implant. Bacterial implantation in this instance can occur at any age and in any potential patient. Additionally, vascular insufficiency can lead to osteomyelitis and most often occurs among diabetic populations. Most commonly, patients acquire osteomyelitis through the contiguous spread of bacteria from a neighboring ulceration or cellulitis. Osteomyelitis in the absence of these entities is extremely rare. Areas that are most prone to ulceration and subsequent bone infection include the digits, metatarsal heads, calcaneus and malleolus.
Traditionally, clinicians have utilized a probe-to-bone test in the clinical evaluation of osteomyelitis. Two studies have evaluated the reliability of the probe-to-bone test in evaluating the true incidence of bone infection. Lavery and colleagues determined that the probe-to-bone test was both sensitive (0.87) and specific (0.91).3 This study also found that the probe-to-bone test had a relatively low positive predictive value (0.57) and a high negative predictive value (0.98), indicating that a negative test could reliably exclude the diagnosis. Grayson confirmed the reliability of the probe-to-bone test in his earlier study.4
One can usually reject osteomyelitis as a differential diagnosis if an open ulceration is not present or a traumatic inoculation did not occur.5 Clinicians should pursue initial laboratory studies, including complete blood count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), for any patient in whom there is suspected infection. If the results of these tests are unremarkable, bone or soft tissue infection are much less likely.6,7
White blood cell counts and oral temperature may not be reliable indicators of the presence of osteomyelitis or soft tissue infection in the patient with diabetes. One study found white blood cell count to be elevated in approximately half of those with positive bone cultures.8 Fever was also present in only 20 percent of the same population. The study found ESR to be a valuable tool in the initial evaluation of the patient with diabetes as it was elevated in 96 percent of these patients.8
The ESR, however, is not beneficial in gauging a response to treatment as the kinetics are too slow. The CRP is better in this regard as values will increase within a few hours of infection and will trend toward baseline values after a week of appropriate therapy.9,10 When evaluating for osteomyelitis in children, ESR and CRP have the best sensitivity and specificity when one uses them in combination.10
Procalcitonin is a relatively new laboratory marker for the determination of osteomyelitis. Secreted by the thyroid gland, procalcitonin is a precursor peptide to calcitonin. Procalcitonin is elevated during an acute infective process and studies have well documented its utility in the prediction of soft tissue infection.10,11 However, one study refuted procalcitonin’s usefulness in diagnosing osteomyelitis within the diabetic population, finding it to be an unreliable indicator.11
One must cautiously consider sinus tract cultures in those with chronic osteomyelitis. When Staphylococcus aureus is the cultured organism from the sinus tract, the results are more reliable. However, sensitivity is still only 60.5 percent and specificity is 45 percent with a positive predictive value of 72.2 percent.12 Generally, sinus tract organisms are much lower in sensitivity (50.9 percent) and specificity (20 percent) when Staph aureus is not the causative agent. Intraoperative bone culture remains more predictive in identifying the causative organisms.
Staphylococcus aureus continues to be the most common pathogen occurring in both traumatic and diabetic bone infections. It can be extremely difficult to treat for a number of reasons. Staphylococcus aureus adhesions interact with thrombin, vitronectin, fibrinogen, fibronectin, collagen, laminin, von Willebrand factor, elastin and bone sialoprotein. It is through these adhesions that colonization occurs.
Additionally, S. aureus contains protein A, toxins and capsular polysaccharides that allow for evasion of host defenses. Exotoxins and hydrolases also promote extracellular matrix destruction and intracellular penetration. Biofilm production also adds to the virulence of this microbe, making it very difficult for antimicrobials to attack and kill.13
Other pathogens commonly cultured in the diabetic foot infection include Streptococcus, Enterococcus, coagulase-negative staphylococci, gram-negative aerobic bacilli and anaerobes. Pseudomonas aeruginosa commonly arises in puncture wounds to the heel, especially in those that develop osteomyelitis. Pathogens such as Staphylococcus aureus, polymicrobial infections, gram-negative aerobic bacilli and anaerobes most commonly occur with traumatic osteomyelitis.13
Antimicrobial therapy remains the primary treatment for most cases of juvenile hematogenous osteomyelitis whereas in chronic osteomyelitis, a focal nidus of infection is often impenetrable to antibiotic therapy. In this instance, pharmaceutical treatment becomes secondary and surgical debridement with irrigation becomes primary. Despite adequate treatment, recurrence rates continue to range between 20 and 30 percent.14 Some recent studies have disputed that surgical intervention is always necessary and suggest that antibiotic therapy alone may be a viable treatment option even for complicated bone infections.15,16 What the literature does not dispute is that deep bone culture is necessary to guide definitive antibiotic therapy.13
Empiric antimicrobial coverage for diabetic osteomyelitis should always include coverage of methicillin resistant Staphylococcus aureus (MRSA). Clinicians can then tailor pharmaceutical therapy toward specific organisms once they acquire culture results. Intravenous therapy should continue for six to 12 weeks unless definitive debridement of infected bone has occurred. At this time, one may shorten the antibiotic course to two weeks.17
Radiography. Plain film radiographs remain necessary in the initial evaluation of bone infection. Early radiographic changes in the patient with osteomyelitis will often be subtle. Lytic osseous changes are often not visible for up to two to three weeks.18 By the time lysis is visible on radiographic images, extensive destruction of the bone has already occurred.
The photos at right demonstrate the rapid changes that can occur when one does not notice bone infection early. The top photo shows very subtle lytic and cortical changes. Within two weeks (see the bottom photo), the proximal phalanx is already showing signs of significant osteolysis, serpiginous changes and cortical dissolution. A study by Boutin and colleagues found radiographic evidence of osteomyelitis in as few as 3 to 5 percent of culture-positive osteomyelitis cases.19
Bone scintigraphy. Classically, osteomyelitis presents with focal hyperperfusion, focal hyperemia and demonstrates positive uptake on all three phases of bone scans. Bone scintigraphy is an early sensitive, but not specific, method of identifying bone infection.20 Nuclear imaging allows abnormalities of bone to be visible weeks or even months earlier than on plain film radiographs. One can cautiously confirm osteomyelitis after obtaining a positive 24-hour scan if no other differentials such as Charcot neuroarthropathy, bone tumor, stress injury or fracture exist. Negative results at three to six hours can effectively rule out osteomyelitis.21
In order to improve specificity, one can obtain indium oxide 111 labeled scans. Sensitivities between 70 and 90 percent occur with labeled leukocyte scanning.22,23 Drawbacks of the indium-111 scans include lower quality image expense, cost and exam complexity.20,24 Tc-HMPAO scans provide higher imaging quality in comparison to indium oxide 111. Leukocyte scans may demonstrate a comparative decrease in uptake as the resolution of osteomyelitis is occurring.25
Magnetic resonance imaging (MRI). One can detect bone edema very clearly on MRI and this is what a clinician should look for when evaluating for bone infection. Radiographs and bone scans will not reveal this information. Bone edema is visible as hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging. Gadolinium can also enhance areas of cellulitis or abscess formation.26
One of the more difficult differential diagnoses when evaluating a patient with diabetes and potential osteomyelitis is Charcot neuroarthropathy. Diagnosis can be difficult and even impossible to delineate, based on plain film radiographs and general nuclear medicine imaging. One can often obtain valuable insight through MRI but the clear differentiation of infection and Charcot neuroarthropathy is still difficult based on MRI evaluation alone. Bone edema can be clearly visible with osteomyelitis and neuroarthropathy.27
It is therefore important to evaluate MRI studies carefully for subtle differences that can lead to a correct diagnosis. Infection is favored as the diagnosis if bone marrow edema is localized within one specific area or bone. Underlying sinus tracts, subchondral cysts, diffuse bone marrow abnormalities or erosions of the bone will also support a diagnosis of bone infection. Osteomyelitis and Charcot neuroarthropathy will demonstrate hypointense signal intensity of bone marrow with T1-weighted images and hyperintense signal intensity with T2-weighted images. When bone edema concentrates to articular surfaces and edema spans multiple joints, Charcot neuroarthropathy is the more likely diagnosis.
Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning. Although FDG-PET would not be a typical study for evaluation of a simple case of osteomyelitis, the test does offer some distinct advantages when attempting to differentiate osteomyelitis from Charcot neuroarthropathy. The FDG-PET has the ability to differentiate these diagnoses on the basis of glucose metabolism. Infection results in higher glucose uptake. Charcot disturbances typically have standardized uptake values of approximately 2 or lower whereas bone infection will result in much higher standardized uptake values in the range of 3 to 7. The FDG-PET scans produce focal, distinct areas of uptake in the individual with osteomyelitis and more diffuse uptake in an individual with Charcot neuroarthropathy.28
One can reliably evaluate patients with metal implants with FDG-PET without complicating artifacts to obscure views, as one would see with MRI. At least one study has found ring PET to be more reliable than hybrid (dual head gamma camera) PET in at least one study since the resolution of ring PET scans is higher than hybrid PET scans.27,28 Ring FDG-PET offers a higher sensitivity and specificity in differentiating Charcot foot from infection in comparison to MRI results.27,28
Physicians rarely utilize FDG-PET clinically, although the benefits are arguable in rare situations. A significant limitation of this imaging modality is its expense, which can range from $2,000 to $8,000 depending on the institution. Ionizing radiation exposure and limited availability of this technology outside of a tertiary care setting are also limitations that can preclude its routine use. Time will tell if this diagnostic modality’s usage will increase. With improvements in practitioner awareness, cost effectiveness and accessibility, its future utility may be invaluable.
One can often treat acute hematogenous osteomyelitis with antibiotics alone. Chronic osteomyelitis traditionally requires irrigation and debridement of necrotic, infected tissue and bone. Adequate surgical debridement can result in large areas devoid of bone. Drug eluting antibiotic beads can fill in these voids.
One of the most commonly utilized materials for antibiotic beads is polymethylmethacrylate (PMMA). One of the disadvantages to using PMMA is that a second surgery is always necessary to remove the beads as they are not absorbable in vivo. Pharmacokinetic profiles of PMMA beads are not ideal as the maximal elution is on day one with a subsequent drop occurring over the following three to four weeks. At this time, insufficient concentrations occur locally. Some evidence exists to support the usage of vancomycin and clindamycin with PMMA beads as levels continue to remain above minimal inhibitory concentration (MIC) at 28 days.29,30 Benefits to these beads include an absence of drainage from the surgical site.
Calcium sulfate is another commonly utilized material for the delivery of local antibiotics. Advantages include ease of access, low cost, safety, a low risk of donor site morbidity and an osteoconductive structure. Disadvantages include sterile sinus tracts that develop as the calcium sulfate beads resorb. Calcium sulfate’s utility as a bone graft substitute, especially in subcutaneous areas, is poor secondary to a limited strength and the production of sinus tracts.31 Of note, serum calcium is not elevated in those individuals with implanted calcium sulfate beads.32
Polylactic acid microspheres have yet to undergo study among human controls although orthopedic surgeons have used it as a structural support for years. Researchers have looked at this modality in rabbits as an antibiotic delivery system and the results are promising. Drug elution qualities with polylactic acid microspheres are superior to their PMMA counterparts and MIC is maintained up to four weeks following implantation. One can also see sterile sinus tracts with this material.32
The single best way to prevent osteomyelitis in the patient with diabetic neuropathy is with appropriate offloading of pressure areas through padding and shoe gear modifications. In addition to these standard protocols, epidermal nerve fiber density testing can allow for the early detection of small-fiber sensory loss in the patient with diabetes, even in those who may not be experiencing clinic symptoms. Early detection of sensory loss can lead to rapid intervention and treatment.
Appropriate treatment with a disease-modifying agent can result in regrowth of nerve fibers, which one can objectively measure through repeated epidermal nerve fiber density testing. When patients receive a disease-modifying agent early in the process of sensory loss, reversal or delay of neuropathy can often occur, thus preventing ulceration, infection and potential limb loss.33
Osteomyelitis remains one of the most important conditions we treat. Preventative care, such as proper shoe gear selection and offloading, remains essential to avoid amputation in our diabetic, vascular-impaired and neuropathic patient populations. Epidermal nerve fiber density testing may have some current and future important benefits in the early diagnosis of neuropathy. A timely diagnosis allows us to begin treatment of the causative factors potentially delaying or preventing the progression of neuropathic symptoms.
Laboratory studies such as ESR and CRP are still useful in evaluating the individual with bone infection. The ESR is reliable for initial evaluation but CRP is better for long-term assessment of the infectious process and response to antibiotics. White blood cell and temperature remain poor indicators of infection among diabetic populations. Radiographic evaluation often lags behind other imaging techniques such as MRI and indium labeled bone scans in the early identification of bone infection. New and emerging imaging modalities such as FDG-PET may allow us more definitive delineation between osteomyelitis and Charcot neuroarthropathy, which continues to remain a diagnostic challenge.
Dr. Hild is a prior resident of the Kaiser Permanente/Cleveland Clinic Foundation in Cleveland.
Dr. Boike is the head of the Podiatry Section in the Foot and Ankle Center of the Orthopaedic and Rheumatology Institute in Cleveland. He is also the Director of the Podiatry Residency Training program at the Cleveland Clinic. Dr. Boike is a Fellow of the American College of Foot and Ankle Surgeons. He presently serves on the Board of Directors of the American Board of Podiatric Surgery.
1. Andersen CA, Roukis TS. The diabetic foot. Surg Clin North Am. 2007; 87(5):1149-1177, x.
2. Shetty AK, Kumar A. Osteomyelitis in adolescents. Adolesc Med State Art Rev. 2007; 18(1):79-94, ix.
3. Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe-to-bone test for diagnosing diabetic foot osteomyelitis: reliable or relic? Diabetes Care. 2007; 30(2):270-274.
4. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing to bone in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients. JAMA. 1995; 273(9):721-723.
5. Botek G, Anderson MA, Taylor R. Charcot neuroarthropathy: An often overlooked complication of diabetes. Cleve Clin J Med. 2010; 77(9):593-599.
6. Judge MS. Infection and neuroarthropathy: the utility of C-reactive protein as a screening tool in the Charcot foot. J Am Podiatr Med Assoc. 2008; 98(1):1-6.
7. Pakarinen TK, Laine HJ, Honkonen SE, Peltonen J, Oksala H, Lahtela J. Charcot arthropathy of the diabetic foot. Current concepts and review of 36 cases. Scand J Surg. 2002; 91(2):195-201.
8. Armstrong DG, Lavery LA, Sariaya M, Ashry H. Leukocytosis is a poor indicator of acute osteomyelitis of the foot in diabetes mellitus. J Foot Ankle Surg. 1996; 35(4):280-283.
9. Hariharan P, Kabrhel C. Sensitivity of erythrocyte sedimentation rate and C-reactive protein for the exclusion of septic arthritis in emergency department patients. J Emerg Med. 2011; 40(4):428-431.
10. Paakkonen M, Kallio MJ, Kallio PE, Peltola H. Sensitivity of erythrocyte sedimentation rate and C-reactive protein in childhood bone and joint infections. Clin Orthop Relat Res. 2010; 468(3):861-866.
11. Mutluoglu M, Uzun G, Ipcioglu OM, et al. Can procalcitonin predict bone infection in people with diabetes with infected foot ulcers? A pilot study. Diabetes Res Clin Pract. 2011; 94(1):53-56.
12. Akinyoola AL, Adegbehingbe OO, Aboderin AO. Therapeutic decision in chronic osteomyelitis: sinus track culture versus intraoperative bone culture. Arch Orthop Trauma Surg. 2009; 129(4):449-453.
13. Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004; 364(9431):369-379.
14. Conterno LO, da Silva Filho CR. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev. 2009(3):CD004439.
15. Embil JM, Rose G, Trepman E, et al. Oral antimicrobial therapy for diabetic foot osteomyelitis. Foot Ankle Int.M 2006; 27(10):771-779.
16. Game FL, Jeffcoate WJ. Primarily non-surgical management of osteomyelitis of the foot in diabetes. Diabetologia. 2008; 51(6):962-967.
17. Bader MS. Diabetic foot infection. Am Fam Physician. 2008; 78(1):71-79.
18. Haas DW, McAndrew MP. Bacterial osteomyelitis in adults: evolving considerations in diagnosis and treatment. Am J Med. 1996; 101(5):550-561.
19. Boutin RD, Brossmann J, Sartoris DJ, Reilly D, Resnick D. Update on imaging of orthopedic infections. Orthop Clin North Am. 1998; 29(1):41-66.
20. Palestro CJ, Love C. Nuclear medicine and diabetic foot infections. Semin Nucl Med. 2009; 39(1):52-65.
21. Yu GV, Hudson JR. Evaluation and treatment of stage 0 Charcot’s neuroarthropathy of the foot and ankle. J Am Podiatr Med Assoc. 2002; 92(4):210-220.
22. Ertugrul BM, Savk O, Ozturk B, Cobanoglu M, Oncu S, Sakarya S. The diagnosis of diabetic foot osteomyelitis: examination findings and laboratory values. Med Sci Monit. 2009; 15(6):CR307-312.
23. Poirier JY, Garin E, Derrien C, et al. Diagnosis of osteomyelitis in the diabetic foot with a 99mTc-HMPAO leucocyte scintigraphy combined with a 99mTc-MDP bone scintigraphy. Diabetes Metab. 2002; 28(6 Pt 1):485-490.
24. Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis. 2008; 47(4):519-527.
25. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis. 1997; 25(6):1318-1326.
26. Chantelau E, Richter A, Schmidt-Grigoriadis P, Scherbaum WA. The diabetic charcot foot: MRI discloses bone stress injury as trigger mechanism of neuroarthropathy. Exp Clin Endocrinol Diabetes. 2006; 114(3):118-123.
27. Basu S, Chryssikos T, Houseni M, et al. Potential role of FDG PET in the setting of diabetic neuro-osteoarthropathy: can it differentiate uncomplicated Charcot’s neuroarthropathy from osteomyelitis and soft-tissue infection? Nucl Med Commun. 2007; 28(6):465-472.
28. Hopfner S, Krolak C, Kessler S, et al. Preoperative imaging of Charcot neuroarthropathy in diabetic patients: comparison of ring PET, hybrid PET, and magnetic resonance imaging. Foot Ankle Int. 2004; 25(12):890-895.
29. Rushton N. Applications of local antibiotic therapy. Eur J Surg Suppl. 1997; (578):27-30.
30. Wilson KJ, Cierny G, Adams KR, Mader JT. Comparative evaluation of the diffusion of tobramycin and cefotaxime out of antibiotic-impregnated polymethylmethacrylate beads. J Orthop Res. 1988; 6(2):279-286.
31. Beuerlein MJ, McKee MD. Calcium sulfates: what is the evidence? J Orthop Trauma. 2010; 24(Suppl 1):S46-51.
32. Kent ME, Rapp RP, Smith KM. Antibiotic beads and osteomyelitis: here today, what’s coming tomorrow? Orthopedics. 2006; 29(7):599-603.
33. Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5’-phosphate. Rev Neurol Dis. 2011; 8(1-2):39-47.
For further reading, see “Emerging Insights In Diagnosing And Treating Osteomyelitis” in the July 2012 issue of Podiatry Today.