Daniel Manicourt

Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions.

OBJECTIVEnTo relate the rate of bone resorption to serum levels of both hyaluronan (HA) and antigenic keratan sulfate (KS) in canine experimental osteoarthritis (OA) and to evaluate the effects of calcitonin on these parameters and the OA lesions of the unstable knee.nnnMETHODSnTwenty-two dogs underwent anterior cruciate ligament transection (ACLT) and 6 dogs underwent sham operation. Urinary pyridinium crosslinks were quantified by high-performance liquid chromatography. Immunoassays quantified hyaluronan (HA) and antigenic KS. Macroscopic and histologic OA lesions were scored. Calcitonin treatment was started on day 14 postsurgery and stopped on either day 49 or day 104 postsurgery. Control dogs and all treated dogs were killed on day 105.nnnRESULTSnAll ACLT joints developed OA. In contrast to sham-operated animals, all operated dogs exhibited an early and sustained rise in the levels of their urinary and serum markers. Calcitonin markedly reduced the levels of these markers and the severity of OA lesions. Furthermore, the longer the period of calcitonin therapy, the lower the score of the OA lesions.nnnCONCLUSIONnBone, synovium, and articular cartilage all appear to be involved in the state of hypermetabolism that develops in unstable joints. Furthermore, the rate of bone resorption increases markedly in the early stages of this OA model and is likely to contribute to cartilage breakdown. Since calcitonin reduced the severity of OA changes, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury.

Effects of tenoxicam and aspirin on the metabolism of proteoglycans and hyaluronan in normal and osteoarthritic human articular cartilage.

1 As nonsteroidal antiinflammatory drugs may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in the metabolism of newly synthesized proteoglycan (PG) and hyaluronan (HA) molecules produced by tenoxicam and aspirin in human normal cartilage explants and in osteoarthritic (OA) cartilage from age‐matched donors. 2 Explants were sampled from the medial femoral condyle and were classified by use of Mankins histological‐histochemical grading system. Cartilage specimens were normal in 10 subjects, exhibited moderate OA (MOA) in 10 and had severe OA (SOA) in 10. 3 Cartilage explants were pulsed with [3H]‐glucosamine and chased in the absence and in the presence of either aspirin (190 μg ml1) or tenoxicam (4–16 μg ml−1). After papain digestion, the labelled chondroitin sulphate ([3H]‐PGs) and HA([3H]‐HA) molecules present in the tissue and media were purified by anion‐exchange chromatography. 4 In normal cartilage as well as in explants with MOA and SOA aspirin reduced more strongly PG and HA synthesis than the loss of [3H]‐HA and [3H]‐PGs. 5 In normal cartilage, tenoxicam did not affect PG metabolism whereas it reduced HA synthesis in a dose‐dependent manner and did not change or even increased the net loss of [3H]‐HA. In contrast, in OA cartilage, tenoxicam produced a stronger reduction in the loss of [3H]‐PGs than in PG synthesis and this decrease occurred at lower concentrations in cartilage with SOA (4–8 μg ml−1) than in cartilage with MOA (8–16 μg ml−1). In cartilage with MOA, the metabolic balance of HA was unaffected by tenoxicam whereas in cartilage with SOA, the drug decreased the loss of [3H]‐HA and concomitantly did not change or even increased HA synthesis. 6 The data obtained in short‐term in vitro cultures indicate that aspirin may produce OA‐like changes in normal cartilage and is likely to worsen the disease process in OA tissue. On the other hand, although tenoxicam may reduce the HA content of normal cartilage, and, in so doing, may produce OA‐like lesions, this drug should not per se accelerate joint failure in OA.

99mTc-labelled immunoglobulin scintigraphy in arthritis: an analysis of synovial fluid activity.

The distribution of 99mTc-labelled human polyclonal non-specific immunoglobulin G (HIG) in the synovial fluid was studied in 14 patients with rheumatoid and non-rheumatoid arthritides. Analysis included the determination of the total activity per ml synovial fluid 6 h post-injection (p.i.) of the tracer as well as of the protein- and cell-bound fractions. At 6 h p.i., > 60% of the injected dose remained in plasma as protein-bound radioactivity. Values in the synovial fluid ranged between 0.001 and 0.009% of the injected dose per ml. Importantly, the synovial fluid to plasma ratio was consistently < 1 (range: 0.09-0.43), which is in the range of ratios observed for endogenous proteins in vivo. Similar values were obtained in samples of synovial tissue obtained at surgery in two patients. These data are consistent with the hypothesis that labelled HIG accumulates in the extracellular fluid (both within the synovial tissue and fluid) by non-specific mechanisms (such as increased blood pool and capillary permeability) and does not equilibrate with circulating plasma proteins in accordance with basic knowledge of synovial physiology. In addition, it was found that most of the activity remained bound to the proteins in the fluid and that cell-binding occurred to a very low degree that cannot be considered an important mechanism of uptake of this radiolabelled agent in vivo. These results provide the first evidence in an in vivo human setting that radiolabelled HIG accumulates mainly by non-specific mechanisms in inflamed joints.

Zoledronic acid for treatment of Paget's disease of bone

Pagets disease of bone is characterised by a focal increase in bone resorption and bone formation. This anarchic metabolism leads to disorganised bone, with bone pain, fragility, deformity and compression of the peripheral or CNS according to the involved site. Quality of life of sufferers is dramatically impaired. Symptomatic therapy trends to relieve pain, but cannot seek to prevent other complications. Only ‘specific’ therapy can fulfil this purpose. Bisphosphonates have become the cornerstone for therapy of Pagets disease in the last 25 years. Progressively stronger bisphosphonates have been launched on the market. The last drug available, zoledronic acid, the most potent of this drug family, can be administered intravenously. It possesses a long-acting efficacy, allowing a follow up on a yearly basis and permitting the chance of a very long remission of the Pagetic lesion. In the long term, prevention of severe complications can be envisaged, with a reasonable pharmacoeconomic cost.

Bisphosphonate therapy for the treatment of postmenopausal osteoporosis

Postmenopausal osteoporosis constitutes the most frequent metabolic bone disease in the elderly. It is complicated by significant morbidity and mortality and its care represents a financial burden for patients and the Social Security system if no effort is made to counteract the occurrence of fractures. Currently, there are therapeutic means that can effectively decrease the incidence of fracture. Bisphosphonates are the main commercially available agents used to reduce the fracture rate. These agents differ in their potency and ability to affect vertebral and nonvertebral fractures as well as clinical and nonclinical fractures rates. Preference should be given to those who are able to fight the clinical consequences of fractures, the main cause of morbidity and mortality in patients. Lack of toxicity is, however, a prerequisite, and tolerance to drugs is central to persistence. Several modes of administration exist, from daily andxa0monthly oral administration to 3-monthly and, probably in the near future,...