Synovial fluid in patients may differ in volume and molecular weight depending on the presence and degree of osteoarthritis. Treatment was not directed at this relationship but at the ability to reduce knee pain in patients both at rest and in activity. Patients with osteoarthritis of the knee with resting visual analogue scale (VAS) pain of >45 mm were included in a randomized, prospective, double-blind cohort followed for 16 weeks.

Patients were randomized at baseline to receive a three intra-articular injection series either of: dual molecular weight (DMW; 580–780 kDa+1.2 to 2.0 million Da) hyaluronic acid (HA); low molecular weight HA (LMW; 500–730 kDa); high molecular weight HA (HMW; 6 million Da); or saline placebo over 3 weeks. Patients completed baseline assessment of rest and walking VAS pain (primary efficacy variable), collection of a 5-point categorical global satisfaction score, and record of adverse events. Two-hundred and twenty-five patients (age 68±8 y) were screened and 200 were randomized to one of the four groups. There were no differences at baseline between groups.

At 4, 12 and 16 weeks respectively, walking VAS pain was significantly improved in all treatment groups vs. placebo: DMW (79.6%, p<0.001; 85.6, p<0.001; 89.3%, p<0.001); LMW (73.6%, p<0.001; 76.4, p<0.001; 81.3%, p<0.001) and HMW (69.1%, p<0.001; 81.0, p<0.001; 79.1%, p< 0.001). Patients in the DMW group had significantly greater improvement (p<0.007) in VAS walking pain by 3 weeks (following the second injection) compared to all groups. This difference was persistent at 16 weeks. Greatest improvement in patients who received the DMW product was actually achieved by the second injection persistent to 16 weeks.

Hyaluronic acid injections were highly satisfactory to patients with each HA series and included a very low rate of local adverse events. This supports previous reports that HA treatment of osteoarthritis of the knee is a safe, effective therapeutic option. Our findings suggest that alteration of MW range may further improve outcomes in these patients.

At 104 weeks, these differences were similar. DMW and LMW had no reported adverse events; HMW had 2 local reactions at 52 weeks and 1 at 104 weeks. There were no serious adverse events. Non-serious adverse events included pain and local swelling at the injection site (21%), erythema at the injection site (12%) and stiffness in the index knee (7%). Intra-articular hyaluronic acid injections using any of LMW, HMW or DMW were highly effective in improving resting and walking pain in patients with osteoarthritis of the knee.

Greater improvement in both rest and activity outcomes was seen in patients who received the DMW product, with concomitantly greater patient satisfaction and fewer use of concomitant therapeutic modalities at 16, 52 and 104 weeks, suggesting that combining a range of MW hyaluronic acid may be advantageous longer term, particularly among active osteoarthritis patients.

The secondary endpoints included: pain at rest, a 10 cm VAS, patient global satisfaction using a 5-point numerical scale, consumption of concomitant medications, number of patients with <45 mm pain at follow up 52 and 104 weeks, and safety through the number of recorded adverse events. Patients received intra-articular injection once weekly for three weeks. Patients were followed up at week 16, 52 and 104.

At 52 weeks, 8 patients in DMW had VAS <45 mm and were not given repeat injections. At 104 weeks, 9 patients had VAS pain <45 mm in the DMW while all in the LMW or HMW groups was >45 mm.

DMW walking pain reduction was significantly greater than either of the LMW or HMW groups.

Again, those who received DMW had significantly greater walking pain reduction compared to the other 2 groups.

At 52 weeks, 8 patients in DMW group had resting VAS <45 mm. DMW had lower (62 mm, P<0.001) compared to LMW (76 mm) and HMW (88 mm) VAS at rest.

Global satisfaction was significantly higher for the DMW group compared to the other groups at 16, 52 and 104 weeks (P<0.005).

Patients in the DMW group had significantly greater improvement at 16, 52 and 104 weeks (P<0.001) compared to the other active treatment groups which did not differ from each other.

Further, fewer concomitant treatments (ie PT, acupuncture) were utilized by those who received DMW compared to the other treatments at all follow up periods.

Similar trends in secondary outcomes were also observed at all time points. Combination of HA of lower and higher ranges of MW with low and high concentrations may provide patients with a more physiologically dynamic HA viscosupplementation and hence a more responsive synovial rheology that improves pain and function in their osteoarthritic knee.

Combination of Sodium Hyaluronate of lower and higher ranges of molecular weight with low and high concentrations, may provide patients with a more physiologically dynamic HA viscosupplementation and hence a more responsive synovial rheology that improves pain and function in their osteoarthritic knee.