A 12-week randomized, double-blind, placebo-controlled multicenter study of choline-stabilized orthosilicic acid in patients with symptomatic knee osteoarthritis

Osteoarthritis (OA) is one of the leading causes of functional disability and compromised quality of life in the elderly worldwide [1]. It is a chronic and slowly progressive disease, with the knee being the most affected weight-bearing joint [2, 3]. OA is a complex disease of joints, characterised by degradation of articular cartilage, changes of the subchondral bone and inflammation, leading to pain and stiffness in the joint [4, 5]. At present, there are no safe OA therapeutic strategies approved that result in a concurrent structural modification and symptom improvement [6, 7]. The treatment of OA is therefore, besides exercise and physiotherapy, still mainly based on analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and surgical procedures [8].

Several risk factors for the development of knee OA have been identified, including age, obesity, injury and genetic profiles. Sex differences in knee OA incidence and prevalence have been reported as well, with females generally at higher risk [7, 9]. Moreover, the meta-analysis performed by Srikanth et al. demonstrated that women tend to have more severe knee OA, particularly after menopausal age [9].

Given the limitations of plain radiography and the high charges for magnetic resonance imaging (MRI), biochemical markers have gained considerable interest over the past 15 years [10, 11]. However, in contrast to the well-established biochemical markers for bone diseases, the value of biomarkers in OA still needs further elucidation [12]. To this respect, Bauer et al. proposed the BIPED – burden of disease, investigative, prognostic, efficacy of intervention and diagnostic – categories, providing a classification system for biochemical markers [13]. Among numerous candidates, C-terminal telopeptide of collagen type II (CTX-II) and cartilage oligomeric matrix protein (COMP), which are two markers of cartilage degradation, have been reported to be the best performing biochemical markers across all BIPED categories [11].

Choline-stabilized orthosilicic acid (ch-OSA) is a specific complex of orthosilicic acid and choline that has been previously demonstrated to stimulate collagen synthesis which positively affects bone turnover [14] as well as surface and mechanical properties of the skin [15]. The choline component of ch-OSA was suggested to contribute to this effect [14], as it lowers plasma homocysteine levels [16]. More specifically, hyperhomocysteinemia has been shown to interfere with collagen cross-linking, leading to connective tissue pathology [17]. To this respect, it may be hypothesized that ch-OSA acts on both cartilage and subchondral bone, consequently rendering it a candidate for the treatment of OA. The aim of this study was to evaluate the symptomatic effects of the oral intake of ch-OSA on knee OA over a 12-week period. Additionally, CTX-II and COMP were analysed to assess the influence of ch-OSA on cartilage degradation.

This is the first clinical study to evaluate the symptom relief effect of ch-OSA in patients with knee OA. Although the intake of the dietary supplement for 12 weeks failed to show a statistically significant benefit over placebo regarding the clinical outcome scores and biomarker values in the per-protocol population, pre-specified subgroup analyses demonstrated a significant effect of ch-OSA in men. Accordingly, WOMAC total, stiffness and physical function scores were significantly reduced in men taking ch-OSA compared to men in the placebo group. While levels of cartilage degradation related biomarkers increased over 12 weeks in men in the placebo group and in women in both groups, these levels were significantly lower in the male ch-OSA group at the final visit. More specifically, the increase in CTX-II was less pronounced and COMP levels remained unchanged. The former suggests that ch-OSA can slow the ongoing progression of cartilage degradation in men.

The management of knee OA remains a major challenge. The key objective is to cease or delay disease progression by controlling cartilage degradation, inflammation and changes of subchondral bone. Nevertheless, most published recommendations primarily aim to control OA symptoms since safe and effective disease-modifying OA drugs (DMOADs) are currently lacking [23‐26]. NSAIDs, for instance, are still among the most commonly used medicines to relieve OA pain, regardless of their well-known side-effects in prolonged therapy [24, 27]. The rationale for studying the effectiveness of ch-OSA in knee OA was consequently based on its previously demonstrated effect on collagen synthesis and its safety in long-term use [14, 15]. The components of ch-OSA, choline and orthosilicic acid (OSA), have both been mentioned with respect to collagen metabolism. Firstly, choline lowers plasma homocysteine levels through its precursor-function in the biochemical conversion of homocysteine to methionine [16]. This reduction positively affects collagen cross-linking, since homocysteine has been shown to interfere with post-translational modifications of collagen through direct and indirect inhibition of lysyl oxidase as well as through down regulation of other genes involved in collagen cross-linking [28]. Indeed, Zhang et al. recently reported elevated serum homocysteine levels in patients with severe OA compared to those with mild OA or healthy controls [29]. Secondly, although the exact role of silicon in bone and connective tissue health remains unclear, its involvement in collagen synthesis and/or stabilisation was recently put forward by Jugdaohsingh et al. [30]. In the present study, the lack of correlation between the change in serum silicon and clinical parameters in men taking ch-OSA, suggests that the effect of ch-OSA cannot be explained as an effect of silicon only. ch-OSA was previously shown to have a positive effect on markers of bone formation, with a significant increase of procollagen type I N-terminal propeptide (PINP) in osteopenic women following a supplementation period of 12 months [14]. In an animal model for postmenopausal osteoporosis, it was demonstrated that ch-OSA partially prevented femoral bone loss [31].

The former supports the hypothesis of a possible effect of ch-OSA on collagen in both cartilage and subchondral bone and consequently on knee OA, particularly in view of increasing evidence of a close interrelationship between subchondral bone and articular cartilage [32, 33]. A positive effect of ch-OSA was indeed confirmed in the present study, already after 12 weeks of treatment, yet only in men. Several hypotheses can be suggested with respect to this gender difference. In general, women report more pain and disability from knee OA [34, 35]. The perception of pain, however, has been demonstrated to depend on the estrogen state. In fact, a low estrogen state was found to be related to hyperalgesia [36]. Consequently, the possibility that the enhanced pain perception masked the effect of ch-OSA in women in the present study cannot be ruled out given the predominance of postmenopausal women (98%) with low endogenous estrogen levels, of which only 7% was on hormone replacement therapy (HRT), a contraceptive, a selective estrogen receptor modulator (SERM) or phytoestrogens. In fact, the mean serum estradiol level of women in the present study was significantly lower compared to that of the male study population.

Besides the fact that postmenopausal women have a different pain perception than man, it has also been confirmed that the severity of knee OA is higher in women as well, and principally in postmenopausal women [9, 37]. Accordingly, urinary CTX-II levels were found to be significantly higher in postmenopausal women than in men [38]. The latter is in correspondence with the trend towards higher baseline CTX-II concentrations observed in – predominantly postmenopausal – women in the present study. Again, decreased estrogen levels might be of importance. Several in vitro, in vivo, genetic and clinical studies indeed designate a potential protective role for estrogens against the development of OA, given the various actions of estrogen on articular tissues [39]. Additionally, considerable experimental models indicate that estrogen deficiency-related increases in bone turnover contribute to the progression of OA [40, 41]. Therefore, in view of the more severe OA forms in women, it can be suggested that the 12-week supplementation period could have been insufficient to result in a clinical benefit.

Given the apparent extensive involvement of estrogen deficiency in the development and progression of knee OA, the use of HRTs or SERMs in women seems plausible. Nevertheless, it has been concluded that the health risks of HRTs may outweigh the potential benefits and that HRTs and SERMs should not be recommended as first-line treatments for OA [42, 43]. Several other pharmacological therapies have been studied with respect to knee OA, including symptomatic slow-acting drugs for OA (SYSADOAs) like glucosamine sulphate, chondroitin sulphate, hyaluronic acid and diacerein. Due to the frequently inconsistent conclusions of these studies, the appropriateness of the former therapies has been recently designated as uncertain [26]. Furthermore, therapeutic approaches that target subchondral bone resorption and/or formation have gained attention [32, 43]. Bisphosphonates, strontium ranelate and calcitonin have been studied in this context, yet none of these treatments has been approved as a DMOAD since evidence of concomitant structural and symptomatic effects is still pending [6, 26]. Additionally, safety issues are of importance, such as the risk of cardiovascular events associated with strontium ranelate [44]. The safety of ch-OSA in prolonged therapy, on the other hand, has been previously demonstrated [45].

Although the relevance of biochemical markers in OA has not yet been proven to be of definite clinical importance, Lotz et al. described their value as secondary outcomes [12]. More specifically, effects on biomarkers can support the primary outcome and provide evidence of pharmacodynamics and mechanisms of action of OA drugs. This is indeed valid in the present study, given that the trend observed for the primary outcome (WOMAC pain) in ch-OSA-treated men was associated with significantly lower biomarker levels, the latter referring to decreased cartilage degradation.

The present study has a number of limitations. Firstly, the evaluation of the magnitude of pain changes is ambiguous. This is related to the relatively high placebo effect – which is however common in OA trials – on the one hand, and to the complicated interpretation of changes evaluated as means rather than individual improvements, on the other hand [46]. Furthermore, the dropout rate was higher than assumed in the sample size calculation (18% in contrast to the postulated 10%), which negatively affected the statistical power in the subgroup analyses, particularly in the male subgroups.

In conclusion, this randomized, placebo-controlled trial provided a first indication of a potential benefit of ch-OSA in the treatment of knee OA in men, particularly in view of the need for a safe long-term treatment. Future research is however needed to further elucidate the observed effects and gender difference since no benefit was found in women. Considering the hypothesis that the 12-week supplementation period may have been insufficient in women, an extension of the treatment duration to at least 6 months would be valuable [47]. Additionally, the inclusion of younger, premenopausal women could, at least in part, contribute to the clarification of the role of estrogen in OA. The potential disease-modifying effects of ch-OSA at the level of the knee, on the other hand, could be evaluated after a prolonged treatment period using reliable and sensitive imaging technologies, such as MRI or high-resolution peripheral quantitative computed tomography (HRpQCT) [43, 48]. Determination of biochemical markers of bone metabolism could also extend the knowledge on the mechanisms of action of ch-OSA. Finally, application of the former research suggestions would also contribute to the identification of different subgroups. These subgroups could then be subjected to separate statistical analyses, which could provide evidence for the further assessment of ch-OSA’s potentials in view of individualized targeted treatments for knee OA.

Choline-stabilized orthosilicic acid did not improve symptoms of knee osteoarthritis in the total study population but a gender effect was observed. A symptomatic improvement was found in men but not in women, after 12 weeks of supplementation, which was associated with a slight but significant reduction of biomarkers which are related to cartilage degradation. In view of the need for a safe long-term therapy for the treatment of knee osteoarthritis, this study provided first evidence on the potential benefit of choline-stabilized orthosilicic acid. Future research is however needed to further elucidate the observed effects and gender difference. Considering the hypothesis that the 12-week supplementation period may have been insufficient in women, an extension of the treatment duration to at least 6 months would be valuable.