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Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXIV | Pages 12 - 12
1 May 2012
Aarvold A Smith J Edwards C Tayton E Gent E Oreffo RC
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Background. Unicameral bone cysts (UBCs) are difficult to treat and have a high recurrence rate. Their pathogenesis is unknown making targeted therapies difficult. Attributed causes include venous and interstitial fluid obstruction, oxygen free radicals, lysosomal enzymes, prostaglandins and genetic factors. Skeletal stem cells (SSCs) are osteoblast precursors critical to bone formation and cyst fluid may influence their growth, however the association between SSCs and cyst fluid has never been investigated. Aim. To investigate the effect of UBC fluid on SSC growth. Methods. Fluid was aspirated from a UBC in the proximal femur of a nine year old boy and centrifuged to isolate the acellular supernatant. SSCs were harvested from bone marrow of a haematologically normal adult and cultured with graded concentrations of cyst fluid in culture media (0,10,25,50%). Cell growth was assessed by alkaline phosphatase staining, and cytokine levels in the fluid were measured. Results. High levels of cytokines known to be chemo-attractive for cells of the of macrophage-monocyte lineage were found, including Macrophage Chemotactic Protein-1 (1853pg/ml), Monokine Induced by γ-interferon (656pg/ml), Macrophage Inflammatory Protein (MIP)-1α (401pg/ml) and MIP-1β (34pg/ml) suggesting a role of osteoclasts in UBC pathogenesis. Furthermore, SSC growth in vitro was reduced in cyst fluid in a concentration dependent manner. Conclusion. This is the first time altered SSC and osteoprogenitor function has been associated with the fluid of a UBC. A negative effect on osteogenesis was demonstrated, the precise mechanisms of which are under investigation, and macrophage-monocyte chemokines suggest high osteoclast activity. This study has indicated a role of the cyst fluid in limiting osteogenesis and bone turnover, which may explain the high failure rate for current interventions. More patients are needed to validate these findings


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXIV | Pages 5 - 5
1 May 2012
Nicolaou N Padman M Bell M Fernandes J
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PURPOSE OF THE STUDY. To assess if prolonged use of Bisphosphonates in Osteogenesis Imperfecta alters the pattern of femoral fractures. Osteogenesis Imperfecta (OI) has been treated with Bisphosphonates for many years with some clear clinical benefits. In adult cohorts there are reports of a new pattern of atraumatic subtrochanteric fractures seen with Bisphosphonate treatment. SUMMARY OF METHODS. This study assesses the location of femoral fractures in a cohort of 176 OI patients treated with Bisphosphonates over a two year period and compares it to a historical control group of 45 managed prior to the advent of this specific treatment. SUMMARY OF RESULTS. review of the radiological digital archive identified 16 femoral fractures in this time period in the Bisphosphonate treated group. All but 2 were within 5cm of the lesser trochanter, and 50% within 3cm. In comparison, the historical group, composed of 26 femoral fractures had a more widespread fracture pattern with the most frequent location being the mid-diaphysis. Many of the sub-trochanteric fractures in the treatment group occurred with minimal trauma, and in some cases without any injury. CONCLUSION. It appears that concerns in the adult osteoporotic population treated with Bisphosphonates are mirrored in Osteogenesis Imperfecta. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs, mediated by abnormal osteoclast and osteoblast function, increase the risk of this type of injury and warrants further investigation


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1134 - 1139
1 Aug 2011
Schindeler A Birke O Yu NYC Morse A Ruys A Baldock PA Little DG

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair.

Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1+/−) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection.

When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1+/− mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07).

These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1.


The Bone & Joint Journal
Vol. 95-B, Issue 8 | Pages 1027 - 1034
1 Aug 2013
Khan T Joseph B

Congenital pseudarthrosis of the tibia (CPT) is a rare but well recognised condition. Obtaining union of the pseudarthrosis in these children is often difficult and may require several surgical procedures. The treatment has changed significantly since the review by Hardinge in 1972, but controversies continue as to the best form of surgical treatment. This paper reviews these controversies.

Cite this article: Bone Joint J 2013;95-B:1027–34.


The Bone & Joint Journal
Vol. 95-B, Issue 4 | Pages 568 - 573
1 Apr 2013
Pichler K Herbert V Schmidt B Fischerauer EE Leithner A Weinberg A

Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and angiogenesis, might play a major role in the response of the growth plate to detrimental loads that lead to overuse injuries in young athletes. In order to test this hypothesis, human growth plate chondrocytes were subjected to mechanical forces equal to either physiological loads, near detrimental or detrimental loads for two hours. In addition, these cells were exposed to physiological loads for up to 24 hours. Changes in the expression of MMPs -2, -3 and -13 were investigated.

We found that expression of MMPs in cultured human growth plate chondrocytes increases in a linear manner with increased duration and intensity of loading. We also showed for the first time that physiological loads have the same effect on growth plate chondrocytes over a long period of time as detrimental loads applied for a short period.

These findings confirm the involvement of MMPs in overuse injuries in children. We suggest that training programmes for immature athletes should be reconsidered in order to avoid detrimental stresses and over-expression of MMPs in the growth plate, and especially to avoid physiological loads becoming detrimental.

Cite this article: Bone Joint J 2013;95-B:568–73.