688899 research-article2016
AMD0010.1177/1179544116688899Clinical Medicine Insights: Arthritis and Musculoskeletal Disordersdel Carmen Caamaño et al
A Double-Blind, Active-Controlled Clinical Trial of Sodium Bicarbonate and Calcium Gluconate in the Treatment of Bilateral Osteoarthritis of the Knee María del Carmen Caamaño1, Sandra García-Padilla1, Miguel Ángel Duarte-Vázquez2, Karla Elena González-Romero2 and Jorge L Rosado1,3
Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders 1–7 © The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav https://doi.org/10.1177/1179544116688899 DOI: 10.1177/1179544116688899
1School
of Natural Sciences, Universidad Autónoma de Querétaro, Santiago de Querétaro, Mexico. of Research and Development, Nucitec S.A. de C.V., Santiago de Querétaro, Mexico. 3 Cindetec A.C., Parque Industrial Querétaro, Santiago de Querétaro, Mexico. 2Department
ABSTRACT Objective: To evaluate the effect of intra-articular injections of sodium bicarbonate with a single (SBCG1) or double dose (SBCG2) of calcium gluconate administered monthly compared with methylprednisolone (MP) for treatment of knee osteoarthritis. Methods: A 3-month, randomized, double-blind clinical trial with patients diagnosed with knee osteoarthritis (OA). The outcome variables were the Western Ontario-McMaster University Osteoarthritis Index (WOMAC) and the Lequesne functional index. Results: After 3 months, all treatments significantly improved in overall WOMAC and Lequesne scores. Mean changes (95% confidence interval) in WOMAC total score and the Lequesne index, respectively, for SBCG1 (−12.5 [−14.3, −10.7]; −9.0 [−11.4, −6.7]) and SBCG2 (−12.3 [−14.3, −10.4]; −8.9 [−10.4, −7.4]) were significantly greater than for MP (−5.0 [−7.2, −2.8]; −3.2 [−4.9, −1.5]) (P 30 Location and grade of OA
Abbreviations: ANOVA, analysis of variance; BMI, body mass index; MP, methylprednisolone; OA, osteoarthritis; SBCG1, sodium bicarbonate and a single dose of calcium gluconate; SBCG2, sodium bicarbonate and a double dose of calcium gluconate. aValues are % or mean (SD). bNo significant differences were found among treatment groups with ANOVA or chi-square tests.
Knee pain was the most common adverse event reported in the 3 treatment groups. None of the reported adverse events was classified as severe.
Discussion
The results of this study confirm that intra-articular injections of sodium bicarbonate and calcium gluconate into the knee joint are significantly more effective in the reduction of knee OA symptoms than intra-articular injections of MP, which is a widely accepted corticosteroid treatment. Both SBCG groups showed a lower WOMAC total score and LFI by approximately 70% and 50%, respectively, compared with baseline values. The improvement based on these indices was significantly different from that of MP, which reduced OA symptoms by about 30% and 20%, respectively. This controlled trial had a duration of 3 months because 3 to 4 months have been recommended as the maximum dose of MP.8 In contrast, monthly SBCG intra-articular injections have been administered safely for 12 months, their beneficial effects continuing for another 6 months.5 An effective OA treatment has been defined as a 30% reduction in pain and functionality symptoms.13,14 Few intra-articular interventions have remarkably surpassed this threshold.15 A recent clinical trial showed reductions with plasma rich in growth factors of 42% and 39% in WOMAC and LFI,
respectively, compared with baseline values after 24 months.14 The treatments evaluated in this study, SBCG1 and SBCG2, in only 3 months reduced pain and functionality scores even more than the effective plasma rich in growth factors. Although it has been assumed that plasma rich in growth factors plays an important role in the regeneration of damaged cartilage, there is no conclusive clinical evidence that supports its mechanism of action. Research evidence indicates that the beneficial effect of plasma rich in growth factors might be due to an anti-inflammatory effect and an inhibition of pain sensation.15 The mechanism of action of the evaluated combination of sodium bicarbonate and calcium gluconate has not been entirely explained, either; the conceptualization and fundamentals of the development of the formulation have been explained previously.5 Briefly, the facts that elucidate its mechanism of action are based on the alkaline pH of sodium bicarbonate, which promotes recovery of intracellular chondrocyte pH, normalizing intracellular metabolic activities,16 leading to a rearrangement of the extracellular matrix.17-19 Calcium gluconate protects the linkage between chondral and bone proteins from the hyperosmotic and acid conditions of the extracellular matrix, allowing for the recovery of the homeostatic mechanisms of the cartilage.20 The effect of both compounds administered together may modify cartilage metabolism by stimulating anabolic activities and decreasing catabolic activities. Clinical evidence from monthly intra-articular injections of SBCG2, which has a higher dose of calcium gluconate, has shown, on average, a slight increase in intra-articular joint space after 12 months of intervention.5 This might suggest that cartilage regeneration, not pain inhibition or antiinflammatory effect, is the mechanism that improves pain and functionality scores. However, to confirm this effect, further studies evaluating magnetic resonance imaging outcomes are needed to support the effectiveness of SBCG in regenerating knee cartilage. The use of SBCG therapy may produce similar or even greater effects than other promising treatments, but the advantage of this novel combination is the nature of its elemental compounds, guaranteeing safe administration in patients with OA for more than 3 injections. Repeated administration of SBCG may help ensure its effectiveness. The results of this study are of particular significance for patients with knee OA, whose mobility and quality of life can be severely impaired. Improving a patient’s ability to work and physical functioning is important, as this helps to maintain independence in activities of daily living, and the functional independence of older adults is associated with decreased mortality and decreased admission into nursing homes and hospitals.21 This clinical trial had some limitations that should be considered. (1) For ethical reasons, the trial design did not include a control group with placebo; thus, the psychologic influence
del Carmen Caamaño et al
5
Table 2. WOMAC subscale and global scores at baseline and after 3 months of treatment.a WOMAC subscales
SBCG1
SBCG2
MP
P value
N
29
34
34
Pain Baseline
5.77 (5.15 to 6.39)
5.78 (5.14 to 6.42)
5.32 (4.56 to 6.08)
After 3 mo
1.87 (1.32 to 2.42)c
2.04 (1.44 to 2.63)c
3.18 (2.30 to 4.06)c
Unadjusted change
−3.90 (−4.66 to −3.14)d
−3.75 (−4.45 to −3.05)d
−2.14 (−2.92 to −1.35)e
0.001
Adjusted changeb
−3.82 (−4.50 to −3.15)d
−3.66 (−4.28 to −3.04)d
−2.29 (−2.92 to −1.67)e
0.002
Stiffness Baseline
5.93 (5.09 to 6.77)
6.44 (5.73 to 7.15)
5.12 (4.06 to 6.18)
After 3 mo
1.71 (1.02 to 2.39)c
2.04 (1.28 to 2.81)c
3.74 (2.69 to 4.78)c
Unadjusted change
−4.22 (−5.07 to −3.38)d
−4.40 (−5.32 to −3.47)d
−1.38 (−2.46 to −0.31)e
AMD0010.1177/1179544116688899Clinical Medicine Insights: Arthritis and Musculoskeletal Disordersdel Carmen Caamaño et al
A Double-Blind, Active-Controlled Clinical Trial of Sodium Bicarbonate and Calcium Gluconate in the Treatment of Bilateral Osteoarthritis of the Knee María del Carmen Caamaño1, Sandra García-Padilla1, Miguel Ángel Duarte-Vázquez2, Karla Elena González-Romero2 and Jorge L Rosado1,3
Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders 1–7 © The Author(s) 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav https://doi.org/10.1177/1179544116688899 DOI: 10.1177/1179544116688899
1School
of Natural Sciences, Universidad Autónoma de Querétaro, Santiago de Querétaro, Mexico. of Research and Development, Nucitec S.A. de C.V., Santiago de Querétaro, Mexico. 3 Cindetec A.C., Parque Industrial Querétaro, Santiago de Querétaro, Mexico. 2Department
ABSTRACT Objective: To evaluate the effect of intra-articular injections of sodium bicarbonate with a single (SBCG1) or double dose (SBCG2) of calcium gluconate administered monthly compared with methylprednisolone (MP) for treatment of knee osteoarthritis. Methods: A 3-month, randomized, double-blind clinical trial with patients diagnosed with knee osteoarthritis (OA). The outcome variables were the Western Ontario-McMaster University Osteoarthritis Index (WOMAC) and the Lequesne functional index. Results: After 3 months, all treatments significantly improved in overall WOMAC and Lequesne scores. Mean changes (95% confidence interval) in WOMAC total score and the Lequesne index, respectively, for SBCG1 (−12.5 [−14.3, −10.7]; −9.0 [−11.4, −6.7]) and SBCG2 (−12.3 [−14.3, −10.4]; −8.9 [−10.4, −7.4]) were significantly greater than for MP (−5.0 [−7.2, −2.8]; −3.2 [−4.9, −1.5]) (P 30 Location and grade of OA
Abbreviations: ANOVA, analysis of variance; BMI, body mass index; MP, methylprednisolone; OA, osteoarthritis; SBCG1, sodium bicarbonate and a single dose of calcium gluconate; SBCG2, sodium bicarbonate and a double dose of calcium gluconate. aValues are % or mean (SD). bNo significant differences were found among treatment groups with ANOVA or chi-square tests.
Knee pain was the most common adverse event reported in the 3 treatment groups. None of the reported adverse events was classified as severe.
Discussion
The results of this study confirm that intra-articular injections of sodium bicarbonate and calcium gluconate into the knee joint are significantly more effective in the reduction of knee OA symptoms than intra-articular injections of MP, which is a widely accepted corticosteroid treatment. Both SBCG groups showed a lower WOMAC total score and LFI by approximately 70% and 50%, respectively, compared with baseline values. The improvement based on these indices was significantly different from that of MP, which reduced OA symptoms by about 30% and 20%, respectively. This controlled trial had a duration of 3 months because 3 to 4 months have been recommended as the maximum dose of MP.8 In contrast, monthly SBCG intra-articular injections have been administered safely for 12 months, their beneficial effects continuing for another 6 months.5 An effective OA treatment has been defined as a 30% reduction in pain and functionality symptoms.13,14 Few intra-articular interventions have remarkably surpassed this threshold.15 A recent clinical trial showed reductions with plasma rich in growth factors of 42% and 39% in WOMAC and LFI,
respectively, compared with baseline values after 24 months.14 The treatments evaluated in this study, SBCG1 and SBCG2, in only 3 months reduced pain and functionality scores even more than the effective plasma rich in growth factors. Although it has been assumed that plasma rich in growth factors plays an important role in the regeneration of damaged cartilage, there is no conclusive clinical evidence that supports its mechanism of action. Research evidence indicates that the beneficial effect of plasma rich in growth factors might be due to an anti-inflammatory effect and an inhibition of pain sensation.15 The mechanism of action of the evaluated combination of sodium bicarbonate and calcium gluconate has not been entirely explained, either; the conceptualization and fundamentals of the development of the formulation have been explained previously.5 Briefly, the facts that elucidate its mechanism of action are based on the alkaline pH of sodium bicarbonate, which promotes recovery of intracellular chondrocyte pH, normalizing intracellular metabolic activities,16 leading to a rearrangement of the extracellular matrix.17-19 Calcium gluconate protects the linkage between chondral and bone proteins from the hyperosmotic and acid conditions of the extracellular matrix, allowing for the recovery of the homeostatic mechanisms of the cartilage.20 The effect of both compounds administered together may modify cartilage metabolism by stimulating anabolic activities and decreasing catabolic activities. Clinical evidence from monthly intra-articular injections of SBCG2, which has a higher dose of calcium gluconate, has shown, on average, a slight increase in intra-articular joint space after 12 months of intervention.5 This might suggest that cartilage regeneration, not pain inhibition or antiinflammatory effect, is the mechanism that improves pain and functionality scores. However, to confirm this effect, further studies evaluating magnetic resonance imaging outcomes are needed to support the effectiveness of SBCG in regenerating knee cartilage. The use of SBCG therapy may produce similar or even greater effects than other promising treatments, but the advantage of this novel combination is the nature of its elemental compounds, guaranteeing safe administration in patients with OA for more than 3 injections. Repeated administration of SBCG may help ensure its effectiveness. The results of this study are of particular significance for patients with knee OA, whose mobility and quality of life can be severely impaired. Improving a patient’s ability to work and physical functioning is important, as this helps to maintain independence in activities of daily living, and the functional independence of older adults is associated with decreased mortality and decreased admission into nursing homes and hospitals.21 This clinical trial had some limitations that should be considered. (1) For ethical reasons, the trial design did not include a control group with placebo; thus, the psychologic influence
del Carmen Caamaño et al
5
Table 2. WOMAC subscale and global scores at baseline and after 3 months of treatment.a WOMAC subscales
SBCG1
SBCG2
MP
P value
N
29
34
34
Pain Baseline
5.77 (5.15 to 6.39)
5.78 (5.14 to 6.42)
5.32 (4.56 to 6.08)
After 3 mo
1.87 (1.32 to 2.42)c
2.04 (1.44 to 2.63)c
3.18 (2.30 to 4.06)c
Unadjusted change
−3.90 (−4.66 to −3.14)d
−3.75 (−4.45 to −3.05)d
−2.14 (−2.92 to −1.35)e
0.001
Adjusted changeb
−3.82 (−4.50 to −3.15)d
−3.66 (−4.28 to −3.04)d
−2.29 (−2.92 to −1.67)e
0.002
Stiffness Baseline
5.93 (5.09 to 6.77)
6.44 (5.73 to 7.15)
5.12 (4.06 to 6.18)
After 3 mo
1.71 (1.02 to 2.39)c
2.04 (1.28 to 2.81)c
3.74 (2.69 to 4.78)c
Unadjusted change
−4.22 (−5.07 to −3.38)d
−4.40 (−5.32 to −3.47)d
−1.38 (−2.46 to −0.31)e
