The purpose of this study was to determine if the natural mineral supplement, sierrasil, would relieve the symptoms of mild to moderate osteoarthritis of the knee in a safe manner. The approach included two doses of the mineral supplement to encompass the anecdotal clinical experience, and to evaluate the inclusion of a botanical extract, cat's claw (vincaria), which had previously been shown to be effective in treating osteoarthritis . Using a randomized, double-blind placebo-controlled multi-center design, it is clear that this mineral supplement is indeed safe. Treatments were efficacious, particularly compared to baseline conditions, but there were clear difficulties in determining a sustained disassociation from placebo. In all sierrasil treated groups there was a significantly faster onset of benefits from initial values (evident from week 1 to 2) compared to placebo (first evident at week 6) but at the conclusion of the study differences between groups was not significant.
While it is of interest that the sierrasil that provided early relief of symptoms the inability to establish sustained significant differences from placebo poses limitations on interpretation. In part this dilemma is the result of the small study group size in this preliminary clinical evaluation. Additionally, an unexpected sharp improvement in primary and secondary assessments in the placebo group at weeks 6 & 8 contributed to the study's limitations. While clearly not in the instructions, subjects may have had expectations that all potential treatments in the randomized protocol would provide benefits and this may account for the placebo response. However, if this were the case one may expect that this placebo effect would be continuous as opposed to an exaggerated response that was observed in the last month of a two month study.
Another important consideration is a potential masking effect of rescue medication use. Rescue medication use was greater in placebo and low dose sierrasil groups, and this may have masked differences between the positive benefits related to treatment and placebo. Total consumption of rescue medication was determined and so it is not possible to link changes in rescue medication to perceived changes in disease activity on a weekly or monthly basis.
With the sierrasil test groups significant reductions in the baseline values of the primary efficacy variable, WOMAC, were evident as early as week 1 with steady improvements with continued administration (Figs. 1, 2, 3, 4). In contrast, placebo treated subjects did not report significant benefits from baseline until week 6. This early onset of benefits is not inconsistent with the in vitro studies demonstrating the protection of human cartilage degradation induced by IL-1β, which was prevented by acute exposure to sierrasil . These human cartilage explant studies also demonstrated that the activation of nitric oxide production, a catabolic pathway [30–32], was attenuated by sierrasil. However, the present study does not directly assess whether protection of against cartilage degradation was associated with the therapies, nor is it likely that a substantial change in joint architecture would occur in this timeframe.
Of note, co-administration of the Uncaria guianensis extract, vincaria, was also chondroprotective in vitro  and associated with a rapid onset of benefits in osteoarthritis as noted in a separate double blind placebo controlled study . Cat's claw has considerable data demonstrating that it is an effective inhibitor of transcription via NF-κB  and this formulation is a quite potent inhibitor of tumor necrosis factor [37, 38]. Thus, both sierrasil and vincaria have the potential to act as disease modifying agents in osteoarthritis although only safety and symptomatic relief were the focal issues of this preliminary clinical study.
As this mineral supplement is relatively unknown it was important to evaluate safety as well as efficacy. In this 2 month study there were no changes in various clinical and laboratory measures of safety. The study design included an evaluation of mineral supplement dose (2 vs. 3 g/day) and the herbomineral combination. The reason for evaluating these somewhat similar doses reflects the anecdotal clinical experience with these doses, which brought suggestions that the higher dose necessitated a more rigorous assessment. There was little difference between these groups although a better defined week 1 and 2 responses with the high dose were evident. The herbomineral combination produced a greater percentage reduction in WOMAC scores and both groups were associated with reduced consumption of rescue medications. This suggests that these approaches provided additional value but a definitive statistical difference to advocate a higher dose or the herbomineral combination was not achieved. However, with a greater subject enrolment these trends would likely have reached significance.
VAS, as an index of pain, was responsive to both treatment as well as placebo. While there were significant differences at 1 month between mineral supplement treatments and placebo this was not statistically evident at 2 months. Indeed there was a trend for an exaggerated placebo effect for many efficacy variables from week 4 to week 8.
VAS is regarded as being a less sensitive index of disease activity than the WOMAC scores, which assess pain as well as stiffness and physical activity/function. The similar trends for earlier symptomatic relief in sierrasil treated subjects in the all three WOMAC subsets, as well as VAS pain, within the first month was noticeable and readily distinguishable from placebo treated individuals (Figs 1, 2, 3, 4, 5). Indeed, the similar trends in these three treatment groups when taken together suggest that this therapeutic approach has a clear early onset of benefits.
The mechanisms by which this natural mineral supplement achieves these actions and benefits is unclear. The study in human explants indicates that it may affect transcriptional events, as indicated by the reduced production of nitric oxide in response to IL-1β. Increased production of nitric oxide under these circumstances is attributed to the expression of inducible nitric oxide synthase [31, 35]. A decade ago we defined that this nitric oxide isoform promoted chronic inflammation [34, 35] and inhibitors alleviate numerous inflammatory conditions including arthritis .
The protection of matrix degradation in response to IL-1 by sierrasil may reflect a reduction in matrix metalloprotease (MMP) production (also transcriptionally regulated in response to IL-1β) or perhaps a direct interference in the activity of MMPs. There is no evidence for the later but is speculated based on the mineral/metal content of sierrasil and the requirement of metals as catalysts in MMPs. Studies by the manufacturer on the acid liberalization of minerals from sierrasil suggest that the majority of the minerals within sierrasil are tightly bound and are not freely bioavailable (data not shown). Additionally, while the ingestion of supplemental minerals may alter the basal nutritional status of the subjects the literature does not provide a clear link between a nutrition-based action of minerals and an effective anti-arthritic therapy . It is speculated that a micromineral action on gene expression or direct interaction with MMPs may be an alternative action to consider.
A critical issue is how to place these findings in a therapeutic perspective. Osteoarthritic patients, and their healthcare providers, are deeply concerned with the recent documentation of an increased risk for cardiovascular disease and stroke with COX-2 inhibitors [4, 5], as well as the significant gastro-intestinal, renal complications and premature deaths associated with non-selective COX inhibitors . With the appreciation that the NSAID class provides symptomatic relief rather that abrogating the disease process , there is a great need for alternatives.
Despite the potential of redox-based botanicals as anti-inflammatory agents , the most commonly used natural product approach to the management of osteoarthritis is glucosamine and chondroitin . While early studies suggested excellent albeit slow-onset responsiveness [15–17], more recent studies have suggested that the benefits offered by glucosamine and chondroitin may have limitations or be variable in nature [13, 18–21]. One recent study suggested that continued use of glucosamine may be unwarranted, even if there were initial benefits . Clarification as to therapeutic potential of this approach is likely to occur when the results of the Glucosamine Arthritis Intervention Trial, with 1588 subjects from 13 centers randomized to 5 treatment groups.
While sierrasil was noted to produce early benefits but it was not clearly established that sustained actions were indistinguishable from placebo. Similar issues have been raised with glucosamine and chondroitin, as well as cetylated fatty acids, where there is some evidence that after 2 months of therapy there are reductions in pain and flexibility but no benefits related to physical function/activity .