Atypical femoral fractures were associated with bisphosphonate use; longer duration of treatment resulted in augmented risk. The incidence of atypical fractures increased over a 12-year period, but the absolute number of such fractures is very small.

To define the potential role of interleukin-6 (IL-6) and its soluble receptor ␣ in cartilage metabolism, we analyzed their effects on tissue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes and chondrocytes. TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble receptor, was first assayed by specific enzyme-linked immunosorbent assay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble receptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA expression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody abolished the effects of the soluble receptor. Finally, supernatant from synoviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induced synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-␣, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.Tissue inhibitors of metalloproteases (TIMPs) 1 are important and specific inhibitors of matrix metalloproteases (MMPs) activity (1). These two classes of molecules play a crucial role in the fine regulation of extracellular matrix turnover, which is altered in most pathological states associated with abnormal extracellular matrix formation (i.e. fibrotic diseases) or tissue destruction (i.e. rheumatoid arthritis). TIMP proteins can bind either to the active site of MMPs, thus blocking access to the substrate, or to the precursor form, blocking further activation.So far, the sequences coding for four human TIMPs (TIMP-1, -2, and -3 and, more recently, TIMP-4) have been identified (1-11). The expression of TIMP-1 proved to be both constitutive and inducible, whereas TIMP-2 appeared to be widely expressed but not inducible (1,12). A recent study indicates that TIMP-3 expression is also constitutive and inducible (13).TIMP-1 expression in differentiated chondrocytes and fibroblasts has been shown to regulated by a few growth factors or cytokines, among which transforming growth factor-␤ (TGF-␤) is considered to be the most important inducer (1,14). On the other hand, catabolic cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-␣ (TNF-␣), the main promoters of MMPs synthesis and matrix degradation, have a marked inhibitory effect on TIMP-1 expression by chondrocytes, although some results have shown that IL-1, depending on the conditions, can either stimulate or inhibit the synthesis of TIMP-1 (15-19). IL-6 was initially considered a pro-inflammatory cytokine like TNF-␣ and IL-1, because of its IL-1-like eff...

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Prescribers should be aware of the possibility of these rare adverse reactions and the prolonged use of bisphosphonates should be reconsidered until long-term robust safety data are available.