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New light on bone formation in CRPS?



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The variability of signs and symptoms of Complex Regional Pain Syndrome (CRPS), may represent between-patient variability in the pathological mechanisms at work. One often forgotten CRPS feature is impaired bone formation yet this has been found in up to fifty percent of patients regardless of disease duration [1]. German Surgeon Paul Sudeck (1866-1945), one of the founding fathers of CRPS, first described impaired bone formation in cases he called “Acute Inflammatory Bone Atrophy” [2]. Recently, Kramer et al. [3] have given this idea impetus with their discovery of elevated markers for bone remodelling in CRPS patients. They found that Osteoprotegerin (OPG) levels were significantly increased in CRPS patients than in either healthy controls or patients with a fracture, but without CRPS.

Osteoprotegerin protects the skeleton from excessive bone destruction [4], but the role of OPG does not stop there. OPG is closely involved in reducing NF-κB activation [4]. NF-κB is a key factor in the inflammatory response to tissue damage and is thereby involved in general physiological mechanisms that play a role in CRPS, such as inflammation, oxidative stress and sensitization [5]. Mind you, just like inflammation, oxidative stress and sensitization, OPG upregulation is what is supposed to happen after trauma. It is the exaggerated nature of the response in CRPS that causes us to view these mechanisms as pathologic. In a sense, the increased levels of OPG in CRPS might be sign of a counter reaction to a derailed inflammatory response. Therefore, the findings of Krämer et al. may have to be viewed in a broader context. Other biomarkers supposed to play a role in CRPS, including TNF-α, IL-1, IL-6 [6], glutamate and glycine [7] and possibly many others we have yet to investigate, need to be included in a balanced approach to the assessment of mechanisms underpinning the clinical manifestation of CRPS patients. In addition, it is important to establish whether these findings also apply to CRPS patients with other limb trauma such as sprains, minor lesion or even spontaneous onset.

Notwithstanding these questions, Krämer et al’s findings lend support to existing treatments that address the exaggerated inflammatory response and altered bone remodeling in CRPS, such as free radical scavengers, corticosteroids [8] and bisphosphonates [9], although the evidence for these treatments remains inconsistent. Furthermore, we should not forget the very important role of activity and weight bearing exercise for CRPS patients which may serve to activate bone formation processes related to this pathway.

About Roberto Perez

Roberto_PerezRoberto Perez was trained as a physical therapist and human movement scientist and is currently Associate Professor for pain, pain therapy and palliative care research at the Anesthesiology department of the VU University Medical Center in Amsterdam, The Netherlands. His fields of expertise are in chronic pain (in particular CRPS and neuropathic pain) and palliative care, with a focus on clinical patient based research, diagnostic and clinimetric aspects of pain and palliative care. He is chairman of the taskforce for the development of multidisciplinary guidelines for CRPS in The Netherlands. He is also a member of the steering committee of the knowledge consortium TREND, where he is program leader for clinical trials. In addition Roberto is also a steering committee member of NeuroSIPE and NeuroControl, and a faculty member of the special Interest Group “Complex Regional pain Syndrome” of IASP. In his spare time Roberto plays double bass and soccer, although his enthusiasm for these substantially exceeds his skill.


[1] Veldman, P., Reynen, H., Arntz, I., & Goris, R. (1993). Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients Lancet, 342 (8878), 1012-1016 DOI: 10.1016/0140-6736(93)92877-V

[2] Sudeck P (2005). On acute inflammatory bone atrophy. Hand Surg Br, 30 (5), 477-81 PMID: 16122585

[3] Krämer HH, Hofbauer LC, Szalay G, Breimhorst M, Eberle T, Zieschang K, Rauner M, Schlereth T, Schreckenberger M, & Birklein F (2014). Osteoprotegerin: A new biomarker for impaired bone metabolism in complex regional pain syndrome? Pain, 155 (5), 889-95 PMID: 24447513

[4] Boyce, B., & Xing, L. (2007). Biology of RANK, RANKL, and osteoprotegerin Arthritis Res Ther, 9 (Suppl 1) DOI: 10.1186/ar2165

[5] de Mos M, Laferrière A, Millecamps M, Pilkington M, Sturkenboom MC, Huygen FJ, Coderre TJ. Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I). J Pain 2009; 10: 1161-9

[6] Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, Huygen FJ, van der Meijden P, Hop WC, Hooijkaas H, & Zijlstra FJ (2006). Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. Mediators Inflamm, 2006 (1) PMID: 16864900

[7] Wesseldijk F, Fekkes D, Huygen FJ, van de Heide-Mulder M, & Zijlstra FJ (2008). Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1. Acta Anaesthesiol Scand, 52 (5), 688-94 PMID: 18419723

[8] Fischer, S., Zuurmond, W., Birklein, F., Loer, S., & Perez, R. (2010). Anti-inflammatory treatment of Complex Regional Pain Syndrome PAIN, 151 (2), 251-256 DOI: 10.1016/j.pain.2010.07.020

[9] Marinus, J., Moseley, G., Birklein, F., Baron, R., Maihöfner, C., Kingery, W., & van Hilten, J. (2011). Clinical features and pathophysiology of complex regional pain syndrome Lancet Neurol, 10 (7), 637-648 DOI: 10.1016/S1474-4422(11)70106-5

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