Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis

Background

Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra-articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment.

Methods

We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events.

Results

Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. Patients who received the intervention experienced a reduction in pain during movement: the mean difference on a 100-mm visual analogue scale was –3.8 mm (95% confidence interval [CI] –9.1 to 1.4 mm) after 2–6 weeks, –4.3 mm (95% CI –7.6 to –0.9 mm) after 10–14 weeks and –7.1 mm (95% CI –11.8 to –2.4 mm) after 22–30 weeks. However, this effect was not compatible with a clinically meaningful difference (expected to be about 15 mm on the visual analogue scale). Furthermore, the effect was exaggerated by trials not reporting an intention-to-treat analysis. No improvement in knee function was observed at any time point. Even so, the effect of hyaluronic acid on knee function was more favourable when allocation was not concealed. Adverse events occurred slightly more often among patients who received the intervention (relative risk 1.08, 95% CI 1.01 to 1.15). Only 4 trials explicitly reported allocation concealment, had blinded outcome assessment and presented intention-to-treat data.

Interpretation

According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit–risk ratio.Osteoarthritis affects about 10% of the population over 55 years of age. Of those, one-quarter are severely disabled.¹ The condition is characterized by degeneration of the articular cartilage and subsequent subchondral bone changes. The underlying mechanisms remain unknown, but the glycosaminoglycan–proteoglycan matrix may play a major role.²Hyaluronic acid, a glycosaminoglycan, is widely used for the treatment of osteoarthritis of the knee. A survey of 2 general practices in the United Kingdom showed that about 15% of patients with osteoarthritis received intra-articular treatment with glucosamine sulfates.³ The costs of such treatment are significant. At present, 1 syringe of hyaluronic acid costs at least Can$130 (US$110). The treatment of knee osteoarthritis is covered by the US Medicare program but not by provincial formularies in Canada. In Austria (which has 8 million inhabitants) more than 10 million euros (approximately US$12 million or Can$15 million) is spent by social insurance programs annually for hyaluronic acid preparations (excluding the cost of application).Hyaluronic acid has beneficial effects in vitro.⁴ Because of its viscoelastic quality, it may replace synovial fluid. Furthermore, it may reduce the perception of pain. Beneficial molecular and cellular effects have also been reported.^2,4 Hyaluronic acid is frequently applied by intra-articular injection, but the evidence concerning its clinical relevance is conflicting. The European League against Rheumatism (EULAR) recommends the intra-articular application of hyaluronic acid as “category 2” evidence (at least 1 controlled study without randomization).⁵ The American College of Rheumatology recommends intra-articular hyaluron therapy for patients with no response to nonpharmacologic therapy and simple analgesics.⁶ In contrast, other specialists have concluded that “hyaluronate sodium is not efficacious” in the treatment of osteoarthritis.⁷ The first state-of-the-art systematic review and meta-analysis was published recently,⁸ and its authors concluded “that intra-articular hyaluronic acid, at best, has a small effect.” We performed a systematic review and meta-analysis of the effect of intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee. In contrast to 2 previous meta-analyses on this subject,^8,9 we used a different approach to data synthesis and interpretation: instead of analyzing a composite effect size over time, we allocated trial data, when possible, to 3 outcome groups that we assumed would be relevant for patients with osteoarthritis. We specifically looked at pain at rest, pain during exercise and joint function as distinct outcomes, measured repeatedly over time. In addition, we assessed adverse events and the impact of both trial quality and molecular mass of the product. This analysis allows us to provide important additional insight into the effects of intra-articular administration of hyaluronic acid for the treatment of osteoarthritis of the knee.     

Involvement of the Shewanella oneidensis decaheme cytochrome MtrA in the periplasmic stability of the beta-barrel protein MtrB

The Shewanella oneidensis outer membrane β-barrel protein MtrB is part of a membrane-spanning protein complex (MtrABC) which is necessary for dissimilatory iron reduction. Quantitative PCR, heterologous gene expression, and mutant studies indicated that MtrA is required for periplasmic stability of MtrB. DegP depletion compensated for this MtrA dependence.     

Do bushmeat consumers have other fish to fry?

The overexploitation of tropical forests for bushmeat and of the oceans for fish are two of the most important threats to global biodiversity. Both phenomena also have manifold implications for human livelihoods and food security. A recent article by Brashares et al. indicates that these two resources are linked: when regional fish supplies are low, local bushmeat hunting intensifies. Although coordinated management of bushmeat and fisheries is thus needed, gaps in our knowledge of these systems must first be filled.     

Spectral and thermodynamic properties of Ag(I), Au(III), Cd(II), Co(II), Fe(III), Hg(II), Mn(II), Ni(II), Pb(II), U(IV), and Zn(II) binding by methanobactin from Methylosinus trichosporium OB3b

Methanobactin (mb) is a novel chromopeptide that appears to function as the extracellular component of a copper acquisition system in methanotrophic bacteria. To examine this potential physiological role, and to distinguish it from iron binding siderophores, the spectral (UV–visible absorption, circular dichroism, fluorescence, and X-ray photoelectron) and thermodynamic properties of metal binding by mb were examined. In the absence of Cu(II) or Cu(I), mb will bind Ag(I), Au(III), Co(II), Cd(II), Fe(III), Hg(II), Mn(II), Ni(II), Pb(II), U(VI), or Zn(II), but not Ba(II), Ca(II), La(II), Mg(II), and Sr(II). The results suggest metals such as Ag(I), Au(III), Hg(II), Pb(II) and possibly U(VI) are bound by a mechanism similar to Cu, whereas the coordination of Co(II), Cd(II), Fe(III), Mn(II), Ni(II) and Zn(II) by mb differs from Cu(II). Consistent with its role as a copper-binding compound or chalkophore, the binding constants of all the metals examined were less than those observed with Cu(II) and copper displaced other metals except Ag(I) and Au(III) bound to mb. However, the binding of different metals by mb suggests that methanotrophic activity also may play a role in either the solubilization or immobilization of many metals in situ.     

Automated reprocessing pipeline for searching heterogeneous mass spectrometric data of the HUPO Brain Proteome Project pilot phase

The newly available techniques for sensitive proteome analysis and the resulting amount of data require a new bioinformatics focus on automatic methods for spectrum reprocessing and peptide/protein validation. Manual validation of results in such studies is not feasible and objective enough for quality relevant interpretation. The necessity for tools enabling an automatic quality control is, therefore, important to produce reliable and comparable data in such big consortia as the Human Proteome Organization Brain Proteome Project. Standards and well-defined processing pipelines are important for these consortia. We show a way for choosing the right database model, through collecting data, processing these with a decoy database and end up with a quality controlled protein list merged from several search engines, including a known false-positive rate.     

Molecular phylogenetics ofCochlearia (Brassicaceae) and allied genera based on nuclear ribosomal ITS DNA sequence analysis contradict traditional concepts of their evolutionary relationship

The systematics and phylogeny of the genusCochlearia and allied genera are unsettled. There are no clearly defined genera and subtribal structures to determine subtribeCochleariinae in respect to subtribeThlaspidinae. The use of morphological data, such as fruit form or embryo characters have resulted in contradictory taxonomic concepts in the past due to their homoplastic nature. We investigated all sections of genusCochlearia recognised in the most common concepts, as well as some genera such asIonopsidium, Bivonaea, Pastorea andThlaspi s. l. pro parte. Previous studies based on molecular data and morphological studies have shown close relationships between taxa from subtribeCochleariinae andThlaspidinae. The Internal Transcribed Spacer regions of the nuclear encoded ribosomal DNA operon and the plastidictrnL intron were sequenced from a number of genera. A molecular phylogeny was derived and compared to traditional classification systems. These data grouped sections ofCochlearia outside theCochlearial Ionopsidium core group and integrated them either closely to genusNoccaea in subtribeThlaspidinae (sect.Pseudosempervivum) or positioned them outside both theCochlearia core group and theThlaspi s. l. clade (sect.Hilliella). The molecular data indicate that subtribal arrangements in tribeLepidieae are artificial and do not reflect evolutionary history. The genusCochlearia is represented by sectionsCochlearia andGlaucocochlearia and the genusIonopsidium should be integrated intoCochlearia.     

Two-dimensional mass spectra generated from the analysis of 15N-labeled and unlabeled peptides for efficient protein identification and de novo peptide sequencing

Protein identification has been greatly facilitated by database searches against protein sequences derived from product ion spectra of peptides. This approach is primarily based on the use of fragment ion mass information contained in a MS/MS spectrum. Unambiguous protein identification from a spectrum with low sequence coverage or poor spectral quality can be a major challenge. We present a two-dimensional (2D) mass spectrometric method in which the numbers of nitrogen atoms in the molecular ion and the fragment ions are used to provide additional discriminating power for much improved protein identification and de novo peptide sequencing. The nitrogen number is determined by analyzing the mass difference of corresponding peak pairs in overlaid spectra of (15)N-labeled and unlabeled peptides. These peptides are produced by enzymatic or chemical cleavage of proteins from cells grown in (15)N-enriched and normal media, respectively. It is demonstrated that, using 2D information, i.e., m/z and its associated nitrogen number, this method can, not only confirm protein identification results generated by MS/MS database searching, but also identify peptides that are not possible to identify by database searching alone. Examples are presented of analyzing Escherichia coli K12 extracts that yielded relatively poor MS/MS spectra, presumably from the digests of low abundance proteins, which can still give positive protein identification using this method. Additionally, this 2D MS method can facilitate spectral interpretation for de novo peptide sequencing and identification of posttranslational or other chemical modifications. We envision that this method should be particularly useful for proteome expression profiling of organelles or cells that can be grown in (15)N-enriched media.     

The effect of prostaglandin E2 on the cardiovascular response to angiotensin II in pregnant rabbits

The rise in arterial blood pressure in response to angiotensin II was studied in the last third of pregnancy in rabbits. The response was compared with that of pregnant rabbits during infusion of prostaglandin E₂ and F_2α. Prostaglandin E₂ significantly diminished the rise in diastolic pressure in response to angiotensin II. Prostaglandin F_2α did not alter the response. Intravenous indomethacin elevated the blood pressure and caused an absolute increase in the pressor response. It did not mediate a change in the percentage rise in blood pressure in response to angiotensin II.     

Olive Pink and the Encounter with the Academy

Olive Pink studied anthropology at the University of Sydney under Professor A.P. Elkin. Although she did fieldwork among the Northern Aranda and Wailbri of Central Australia, she became disenchanted with anthropology and lived a reclusive life in Alice Springs. In this paper I present a brief outline of her life, particularly during the 1930's I point to the problems she encountered and suggested that she needs to be relocated within her discipline.