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Rheumatology Advance Access originally published online on September 26, 2006
Rheumatology 2007 46(3):523-528; doi:10.1093/rheumatology/kel302
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Synovial fluid metabolites in osteonecrosis

K. M. Huffman, J. R. Bowers1, Z. Dailiana2, J. L. Huebner3, J. R. Urbaniak1 and V. B. Kraus3

Physical Medicine and Rehabilitation Service, Durham Veterans Affairs Medical Center, 1Department of Orthopedic Surgery, Duke University Medical Center, Durham, NC, 2Department of Orthopaedic Surgery, Medical School, University of Thessalia, 41222 Larissa, Greece and 3Division of Rheumatology, Department of Medicine, Duke University Medical Center, Durham NC, USA.

Correspondence to: Virginia Byers Kraus, MD, PhD, Box 3416, Duke University Medical Center, Durham, NC 27710, USA. E-mail: vbk{at}duke.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Osteonecrosis of the femoral head results from interruption of the vascular supply and eventual death of the cellular portion of bone. Effective methods of monitoring response to treatment are needed. Our aim was to evaluate synovial fluid metabolites, glucose and lactate, as biomarkers in a canine model of osteonecrosis.

Methods. Osteonecrosis was cryosurgically induced in the right femoral head while the left hip served as control (n = 31). Animals either underwent no further intervention (n = 10), vascular endothelial growth factor (VEGF) injections (n = 4), placement of a vascularized bone graft (n = 6), a combination of VEGF microinjection and vascularized graft placement (n = 5), or treatment with daily oral alendronate (n = 6). After 12 weeks, synovial fluid from each hip joint was obtained for glucose and lactate concentrations.

Results. Joints with surgically induced osteonecrosis demonstrated decreased synovial fluid concentrations of glucose (P < 0.05) and elevated concentrations of lactate (P < 0.05) relative to contralateral control hips. When animals were treated with VEGF, the vascularized graft placement, or vascularized graft and VEGF, there were no differences in the synovial fluid concentrations of these metabolites between cryoablated and control hips. In contrast, alendronate did not normalize the concentration of these synovial fluid metabolites in the cryoablated hips.

Conclusions. Osteonecrosis of the femoral head is associated with alterations in synovial fluid glucose and lactate, reflecting anaerobic metabolism. These metabolites may serve as useful tools for monitoring response to revascularization therapies.

KEY WORDS: Osteonecrosis, Synovial fluid, Synovial fluid metabolites, Glucose, Lactate, Vascular endothelial growth factor, Vascularized bone graft, Alendronate, Canine model


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Osteonecrosis, also known as avascular necrosis, is death of the cellular portion of bone due to an interruption in the vascular supply. While osteonecrosis can occur in many anatomical locations, the femoral head is most commonly affected. Osteonecrosis is a relatively common condition, with an estimated 10 000–20 000 new cases in the Unites States each year, occurring particularly in younger individuals. Treatment of osteonecrosis has traditionally relied upon joint replacement for severe cases, accounting for 10% of total hip replacements [1, 2], with 80% of joint replacements for osteonecrosis occurring in individuals ≤50 years [2]. To provide alternatives, especially in young individuals, to multiple joint replacements throughout their life span, joint-preserving treatment options have become increasingly popular. These include core decompression, bone grafting, osteotomy and free vascular graft placement [3]. Pharmacological treatments for osteonecrosis are also under investigation and include vascular endothelial growth factor (VEGF) and bisphosphonates. Sensitive methods of monitoring the effectiveness of these treatment methods are needed.

One potential means of monitoring progress of joint-preserving treatments for osteonecrosis involves analysis of potential biomarkers in synovial fluid. Several studies suggest that this may be a promising avenue of investigation [4–7]. Synovial fluid concentrations of cartilage oligomeric matrix protein and keratan sulphate, reflecting severity of chondral damage, are reported to be higher in hips with osteonecrosis compared with osteoarthritis [4]. In addition, synovial fluid concentrations of various other cartilage-derived molecules may be useful biomarkers for osteonecrosis, including chondrotin-6-sulphate [4, 6], carboxy-terminal type II procollagen peptide, matrix metalloproteinase 3 [5] and the chondrocyte protein YKL-40 [7]. We hypothesized that synovial fluid metabolites related to anaerobic metabolism, glucose and lactate, might reflect even earlier events in the pathogenesis of osteonecrosis and potentially reflect response to treatments designed to improve vascularization or diminish bone resorption. We, therefore, evaluated these two metabolites in a canine model of surgically induced osteonecrosis of the femoral head.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Surgical induction of osteonecrosis
Thirty-one beagles (11–17 kg), aged on average 41 months at the beginning of the study, were obtained from a standard laboratory supplier (LBL Kennels, Reelsville, IN, USA). Osteonecrosis was induced in the right femoral head as previously described [8, 9]. After induction of general anaesthesia, the right lateral subtrochanteric region was surgically exposed. Using fluoroscopy, a 3.5 mm hole was drilled in the centre of the femoral head and a 3 mm diameter cryoprobe (CMS Accuprobe 620; Cryomedical Sciences Inc., Rockville, MD, USA) was inserted into the drilled hole. Using liquid nitrogen circulating within, the probe was cooled to –175°C for 4 min and then allowed to thaw to 0°C. This freeze-thaw cycle was repeated once. After irrigation, the wound was closed in layers, and the animals were allowed to recover from general anaesthesia. For each animal, the left femoral head served as control.

Interventions
Animals were randomly allocated into one of five groups. Ten animals underwent induction of osteonecrosis of the femoral head as described in the previous paragraph with no further intervention. In four canines, immediately after induction of osteonecrosis, a 1 ml bolus injection of VEGF [500 µg/ml; (Genentech, Inc., South San Francisco, CA, USA)] was administered into the drill hole over a few seconds. Six animals underwent placement of a vascularized fibular pedicled graft. Specifically, the proximal two-thirds of the fibula with the popliteal vascular bundle were harvested as a vascularized bone graft. After harvest, the fibula was trimmed of muscular attachments, and inserted into the drilled hole within the femoral head. The attached vessels were rotated with the fibula and the pedicled graft was secured in place with a Kirschner wire [10]. Additionally, five animals underwent administration of 1 ml bolus VEGF (500 µg/ml) injection followed by vascularized bone graft placement. Six animals were treated with 10 mg/day of oral alendronate (Merck, Whitehouse Station, NJ, USA) for 12 weeks.

All animals were killed 3 months after surgery. The Institutional Animal Care and Use Committee approved all procedures. Surgically removed femoral heads were formalin-fixed and paraffin-embedded. Standard 5 µm sections were stained with Masson–Goldner trichrome or toluidine blue.

Synovial fluid collection
After euthanasia, synovial fluid was collected from both right and left hip joints using a procedure we previously described and successfully implemented for joints of guinea pigs [11]. Briefly, a piece of tared Whatman #1 filter paper was placed into the joint to absorb the synovial fluid. The synovial fluid volume was calculated using weights of the filter paper pre- and post-synovial fluid application. The filter paper was then incubated overnight at 4°C in a 10-fold excess of normal saline (0.15 M NaCl). After incubation and centrifugation (3500 rpm, 10 min) the supernatant was removed and stored at –20°C prior to analysis.

Metabolite measurement
Synovial fluid and serum metabolites were analysed within 1 month of sample acquisition using a CMA600 microdialysis analyser (CMA Microdialysis, Solna, Sweden). Glucose and lactate were detected by colorimetry using glucose oxidase and lactate oxidase, respectively (CMA Microdialysis). Serum metabolites were analysed after proteins were removed via centrifugal filtration (3000 rpm, 10 min) with a 10 kDa-cutoff polyethersulfone membrane (Centricon, Millipore, Billerica, MA, USA).

Data analysis
Statistics were performed with SAS Enterprise Guide Version 8.2 (Cary, NC, USA). Descriptive data were evaluated for each metabolite. Wilcoxon signed rank sum tests were used to evaluate the difference in metabolites between treated and control joints. Specifically, change scores were created for each metabolite as follows: operated joint metabolite concentration minus non-operated contralateral joint metabolite concentration divided by the non-operated joint metabolite concentration. Significance was established at a P-value of 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Animals underwent surgical procedures to induce osteonecrosis of the femoral head as described above. Necrosis extended radially into the femoral head approximately 5 mm around the hole created for the insertion of the cryoprobe (Fig. 1A, B). There was no evidence of infection at the time of tissue harvest. Representative sections of formalin-fixed, paraffin-embedded femoral heads from untreated and treated canines are depicted in Fig. 1C–F. In animals with surgically induced osteonecrosis, histological sections displayed thinning of articular cartilage with mild proteoglycan loss, particularly of the calcified cartilage layer. Additionally, subchondral bone demonstrated disruption of the normal architecture with apparent trabecular loss and hypocellular marrow. In contrast, the cartilage and bone histology appeared normal in animals treated with the vascularized bone graft.


Figure 1
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  		FIG. 1. (A,B) Femoral head displaying tract of cryoprobe to induce osteonecrosis. Representative photograph of surgically induced osteonecrosis of the femoral head. The tract of the cryoprobe is indicated by the arrow. B demonstrates collapse of necrotic trabeculae around the tip of the drill hole (non-decalcified Masson–Goldner Trichrome stain, magnification x2.5). (C–F) Representative histology of osteonecrotic and treated femoral heads. (C,D) Representative toluidine blue stained section of a canine femoral head with untreated osteonecrosis (killed at 3 months) depicting thin cartilage, mild proteoglycan loss, particularly in the calcified cartilage layer, trabecular loss, and paucicellular fibrous stroma in the bone marrow space. (E,F) Representative toluidine blue stained section of subchondral canine femoral head that underwent osteonecrosis and concomitant treatment with free vascularized fibular graft, killed at 3 months. This treated femoral head notably had cartilage of appropriate thickness and proteoglycan content, viable trabeculae, and normal haematopoietic cells and adipocytes in the bone marrow. C and E: 2x objective, magnification bar = 1 mm; D and F: 10x objective, magnification bar = 100 µm.

 
Relative to the non-operated, contralateral joints, joints with surgically induced osteonecrosis of the femoral head had significantly lower concentrations of synovial fluid glucose (P < 0.03, Fig. 2A). This decrease in synovial fluid glucose concentrations was normalized by treatment of the femoral head, immediately following the induction of osteonecrosis, with VEGF microinjection (P < 1.0), vascularized fibular bone graft insertion (P < 0.16), or a combination of VEGF microinjection and vascularized fibular bone graft insertion (P < 0.63, Fig. 2A). In contrast, treatment of the osteonecrotic femoral head with alendronate did not prevent the decline in synovial fluid glucose following cryoablation (P < 0.03, Fig. 2A).


Figure 2
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  		FIG. 2. Synovial fluid metabolite concentrations. Synovial fluid metabolite concentrations in operated (osteonecrotic) hips treated with one of five interventions as follows: osteonecrosis without further intervention (n = 10), or after treatment with vascular endothelial growth factor (VEGF) injection (n = 4), vascularized fibular graft (n = 6), combination of VEGF and vascularized fibular graft (n = 5) or alendronate (n = 6). Data are depicted as % control (i.e. relative to the metabolite level in the contralateral non-operated hip) represented for reference by the dotted line at 100%. The bars represent standard error. The asterisk indicates a significant difference between operated and non-operated hips (P < 0.05). (A) Synovial fluid glucose concentrations (non-cryoablated control hip mean glucose concentration was 4.0 mmol/l). (B) Synovial fluid lactate concentrations (non-cryoablated control hip mean lactate concentration was 6.4 mmol/l).

 
Lactate demonstrated a similar but inverse response in osteonecrotic joints. Lactate concentrations were significantly increased in synovial fluid from cryoablated hips relative to control hips (P < 0.002, Fig. 2B). Again, this difference in lactate concentrations was ameliorated by VEGF microinjection (P < 0.63), vascularized fibular bone graft insertion (P < 0.69), or a combination of VEGF microinjection and vascularized fibular bone graft placement (P < 0.81, Fig. 2B). Lactate concentrations were not normalized with alendronate treatment (P < 0.03, Fig. 2B).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
We discovered that surgically induced osteonecrosis of the femoral head produced a decrease in synovial fluid glucose concentrations and an increase in synovial fluid lactate concentrations of affected joints. Revascularization procedures, including VEGF microinjection, vascularized bone graft insertion and a combination of both of these treatments, normalized synovial fluid concentrations of these metabolites while treatment with a bone anti-resorptive agent did not.

Lactate is an established marker of anaerobic metabolism [12]. Elevated concentrations of synovial fluid lactate have been described in joints with effusions corresponding to elevated intra-articular pressures, believed responsible for decreasing capillary blood flow and producing an anaerobic metabolism within the synovium [13]. The decline in synovial fluid glucose with induction of osteonecrosis is also compatible with anaerobic metabolism. However, since glucose serves as a precursor for both aerobic and anaerobic metabolism, by itself, a change in glucose concentration is less helpful as a specific marker of anaerobic metabolism. An elevated concentration of synovial fluid lactate has been suggested as a disease activity biomarker for rheumatoid arthritis [14–16], osteoarthritis [17] and most particularly septic arthritis [12, 18–23]. To our knowledge, this is the first description of elevated synovial fluid lactate and suppressed synovial fluid glucose as biomarkers for osteonecrosis of the femoral head. Notably, the range of synovial fluid lactate concentrations in our model of osteonecrosis (5.4–13.3 mmol/l, mean = 8.3 mmol/l) tended to be intermediate between those reported for non-septic arthritis and the high levels reported in association with septic arthritis [23]. Moreover, relative to the modest alterations shown here, we would expect septic arthritis to produce a more profound decrease in glucose concentrations [23, 24]. Nonetheless, when infection is suspected, routine synovial fluid analyses should include haematological studies, Gram stain and culture.

These metabolites might possibly be evaluated to provide insight into the pathogenesis of other conditions normally considered in the differential diagnosis of hip pain such as transient osteoporosis. Early in its course, radiographic findings can be very similar to those of osteonecrosis [25, 26]. However, transient osteoporosis follows a self-limited course and should be conservatively managed while osteonecrosis often progresses to joint collapse and typically requires surgical treatment. Controversy exists regarding whether transient osteoporosis is an early, reversible stage of osteonecrosis [27], or possibly an early but reversible change in bone metabolism heralding osteoarthritis. Thus, a set of biomarkers that could provide insight into the pathogenesis of this condition could prove useful. If transient osteoporosis represents an early and reversible form of osteonecrosis we would expect similar, although reversible, changes in these metabolites.

Most importantly, the normalization of these synovial fluid metabolite concentrations in response to surgical or pharmacological revascularization procedures suggests that these markers may be useful for monitoring the success of joint-preserving treatments for osteonecrosis. While treatment of osteonecrosis has traditionally relied on joint replacement in late stages, and core decompression for earlier stages, our results demonstrate the potential effectiveness of vascularized graft placement. Vascularized graft placement prevented anaerobic metabolism of the femoral head, as reflected by the adjacent synovial fluid, following an osteonecrosis inducing insult. In retrospective case–control analyses of pre-collapsed lesions, vascularized bone graft placement appeared to result in clinical outcomes superior to non-vascularized graft placement [28, 29] and core decompression [30, 31]. An additional retrospective cohort analysis suggested that vascularized graft placements in post-collapsed, pre-degenerative hips, may delay and potentially prevent, total hip replacement [32].

As demonstrated in animal models, the angiogenic growth factor VEGF, introduced via gene therapy [33, 34] or direct microinjection [35], is also a promising treatment of osteonecrosis. VEGF, administered immediately after cryoablation, normalized synovial fluid glucose and lactate concentrations, both alone, and in combination with vascularized graft placement, suggesting the ability to prevent necrosis. The normalization of synovial fluid glucose and lactate concentrations in this study is even more remarkable given the recognized proinflammatory effects of VEGF [36]. Although we have shown that alendronate improved bone density of osteonecrotic hips [9], and bisphosphonates may prevent femoral head collapse in patients with osteonecrosis [37, 38], the results shown here imply that bisphosphonates did not enhance the vascular regeneration process. Future studies addressing the role of combining bisphosphonate treatment with revascularization for osteonecrosis appear warranted.

Currently, bone scan [39], computed tomography scanning [40] and magnetic resonance imaging [41] may be useful for monitoring response to revascularization procedures. Here, we demonstrate that amelioration of elevated lactate and depressed glucose within synovial fluid may serve as a surrogate for successful revascularization of the femoral head. Although this animal model of osteonecrosis is rapid in onset, it mimics the histological findings reported in man and represents early Ficat Stage II osteonecrosis [8]. Therefore, we believe this to be a very useful model system for pre-clinical investigations of this disease. Further work is required to evaluate these metabolites relative to quantitative assessment of histological changes in this model. This technique appears promising for enhancing current modalities of monitoring response to treatments for osteonecrosis.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
Special thanks to Dr Leigh Thorne and Dr Lubna Khaldi for assistance with histology and Susan Reeves of Duke Photopath for assistance with photomicrographs.

Supported by NIH/NIAMS grant RO1 AR48769 and NIH/NIA Claude D. Pepper OAIC 2P60 AG11268

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 17 April 2006; revised version accepted 18 July 2006.
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