Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing.

Although statins are widely prescribed as cholesterol-lowering drugs, a number of studies suggest that these compounds may have anabolic effects on bone. Our aim was to assess whether simvastatin affects the rate of fracture healing in humans. A prospective, double-blind, randomized controlled trial was performed. Individuals who had sustained an undisplaced, extra-articular fracture of the distal radial metaphysis were recruited from a trauma clinic. Patients were randomized to receive simvastatin 20 mg once daily or a placebo. Regular clinical and radiological follow-up was undertaken for a 12 week period. Dual-energy X-ray absorptiometry assessment of bone mineral density was conducted at 2 and 12 weeks postinjury. Biochemical markers of bone turnover were assayed during the study period. Time to fracture union was defined as the time to cortical bridging in four cortices on plain radiographs. In addition, the rate of trabecular union was assessed. Eighty patients were recruited, of which 62 completed the study (31 in each group). Study cohorts were matched for age and gender. For patients receiving simvastatin therapy, the mean time to fracture union was 71.6 days (SD 22.2 days, SEM 3.8 days). This compared to 71.3 days (SD 21.3, SEM 4.1 days) for the control cohort (p = 0.6481). There was no significant difference between bone mineral density or bone biochemical markers between groups (p > 0.05). Despite promising results from in vivo and in vitro animal studies, simvastatin at a treatment dose of 20 mg once daily does not affect the rate of fracture healing in humans.

Neutralisation of TGF beta or binding of VLA-4 to fibronectin prevents rat tendon adhesion following transection.

Following tendon injury, severe loss of function often occurs either as a result of obliteration of the synovial canal with fibrous scar tissue or from rupture of the repaired tendon. The role of cell engineering in tendon repair is to promote strong and rapid healing of tendon whilst at the same time facilitating rapid reconstitution of the synovial canal. Modification of the immediate inflammatory response around healing tendon has been found to be of value. Experimentally this has been achieved by neutralisation of transforming growth factor-beta over the first 3 days following injury, or by blockade of inflammatory cell binding to the CS-1 locus on fibronectin with an anti-VLA-4 antibody, or with the synthetic VLA-4 inhibitor, CS-1 peptide, in a rat model of tendon transection. It is concluded from this pilot study that the treatments described hold promise in improving outcomes of the common clinical problem of tendon injury in man.

Single dose of inducible nitric oxide synthase inhibitor induces prolonged inflammatory cell accumulation and fibrosis around injured tendon and synovium.

The aim of the current study was to investigate the effect of inhibition of nitric oxide (NO) production after injury on inflammatory cell accumulation and fibrosis around digital flexor tendon and synovium. A standard crush injury was applied to the flexor tendons of the middle digit of the hindpaw and the overlying muscle and synovium of female Wistar rats. Thirty animals received an intraperitoneal injection of either isotonic saline or N(G)-nitro-l-arginine methyl ester (L-NAME; 5 mg/kg) immediately following the crush injury, and five animals were then sacrificed at various intervals and the paws processed for histology. Another group of five animals was sacrificed after 3 days for nitrite determinations. The results showed that nitrite production and hence NO synthase activity is doubled at the acute phase of tendon wound healing, and we can prevent this by administering a single dose of L-NAME immediately after injury. The incidence and severity of fibrocellular adhesions between tendon and synovium was much more marked in animals treated with L-NAME. Treatment with L-NAME elicited a chronic inflammatory response characterised by a persistent and extraordinarily severe accumulation of large numbers of inflammatory cells in the subcutaneous tissues, in muscle and in tendon. These findings indicate that in the case of injured tendon and synovium, NO could act to protect the healing tissue from an uncontrolled inflammatory response.

Expression of nitric oxide synthase and transforming growth factor-beta in crush-injured tendon and synovium.

This study examined the expression of inducible nitric oxide synthase (iNOS) and transforming growth factor-beta (TGF-beta) in macrophage infiltrates within crush-injured digital flexor tendon and synovium of control rats and rats treated with N(G)-nitro-1-arginine methyl ester (L-NAME) (5 mg/kg). Release of TGF-beta from organ cultures of tendon, muscle, and synovium, and the effects of L-NAME treatment (in vitro and in vivo), on adhesion of peritoneal macrophages to epitenon monolayers were also investigated. The results showed that during normal tendon healing the levels of TGF-beta are high at first and gradually decrease after 3 weeks of injury to slightly above control uninjured levels. However, when L-NAME was administered at the time of injury, the macrophage infiltrates were expressing high levels of TGF-beta even at 5 weeks after the injury, with no evidence of reduction. In the standard injury, iNOS activity was greatest at the acute phase of the inflammatory response and then gradually returned to normal. Treatment with L-NAME, however, resulted in inhibition of iNOS activity at 3 days and a reduction in the activity at the later time points examined after injury. We also found greatly increased levels of adhesion of peritoneal macrophages from L-NAME-treated rats to epitenon monolayers in vitro, which reflect a chronic imbalance in expression of TGF-beta, which is overexpressed, and nitric oxide, which is underexpressed. The results of the current study show that formation of nitric oxide is an important event in the course of tendon healing since its inhibition results in chronic inflammation and fibrosis due to an imbalance in TGF-beta expression in vivo.