Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme have recently been shown to stimulate bone formation in rodents both in vitro and in vivo. In bone cells, these inhibitors increase the gene expression of bone morphogenetic protein-2, which is an autocrine-paracrine factor for osteoblast differentiation. The findings that statins increase bone formation and bone mass in rodents suggest a potential new action for these compounds, which may be beneficial in patients with established osteoporosis where marked bone loss has occurred. Recent clinical data suggest that they may reduce the risk of fracture in patients taking these drugs.

Background Hydroxymethylglutaryl coenzyme A reductase inhibitors increase new bone formation in vitro and in rodents. Results of epidemiologic analyses evaluating the association between use of these cholesterol-lowering drugs, bone mineral density and fracture have been mixed. Methods Women (n = 24) with osteopenia, assessed by broad band ultrasound attenuation, were randomized to simvastatin 20 mg, 40 mg or identical-appearing placebo for 12 weeks. Fasting lipid profiles and biochemical markers of bone formation (bone-specific alkaline phosphatase) and resorption (N-telopeptides and C-terminal propeptide of type 1 collagen) were measured at baseline, 6 and 12 weeks. Results Plasma low density lipoprotein-cholesterol concentration fell 7%, 39% (p < 0.01 vs baseline) and 47% (p < 0.01 vs baseline) after 12 weeks of treatment with placebo, simvastatin 20 mg and 40 mg, respectively. At baseline, bone marker concentrations were similar in the three treatment groups. At 6 and 12 weeks, bone marker concentrations were not different from baseline, and no significant differences in bone marker concentrations were observed between treatment groups at either 6 or 12 weeks. Conclusion Among osteopenic women, treatment with simvastatin for 12 weeks did not affect markers of bone formation or resorption.

Inflammatory arthritides are commonly characterized by localized and generalized bone loss. Localized bone loss in the form of joint erosions and periarticular osteopenia is a hallmark of rheumatoid arthritis, the prototype of inflammatory arthritis. Recent studies have highlighted the importance of receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast activation by inflammatory cells and subsequent bone loss. In this article, we review the pathogenesis of inflammatory bone loss and explore the possible therapeutic interventions to prevent it.

Background Although the role of the osteoclast in bone resorption is becoming better understood, much remains to be learned about osteoclastogenesis and the exact mechanism of action of anti-resorbing agents such as 17β-estradiol. This study investigated bone and morphologic osteoclast alterations following long-term estrogen administration to the B6D2F1 mouse. B6D2F1 mice aged 4-5 weeks were exposed to high levels of estrogen via implanted silastic tubing for at least 12 weeks; controls received empty tubing. Femurs of control and treated mice were assessed with radiology, quantitative histomorphometry and transmission electron microscopy. Results After 8 weeks of treatment, there was radiologic evidence of severe osteosclerosis and 86% of femoral marrow space was replaced with bone. After 12 weeks histologic studies of treated animals revealed that osteoclasts were positive for tartrate-resistant acid phosphatase but showed markedly abnormal ultrastructure which prevented successful bone resorption. Conclusions Findings extend our understanding of osteoclast structure and function in the mouse exposed in vivo to high doses of estrogen. Ultrastructural examination showed that osteoclasts from estrogen-treated mice were unable to seal against the bone surface and were unable to form ruffled borders.

Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.

Background Bone morphogenetic proteins (BMPs) and transforming growth factor-βs (TGF-βs) are important regulators of bone repair and regeneration. BMP-2 and TGF-β1 have been shown to inhibit gap junctional intercellular communication (GJIC) in MC3T3-E1 cells. Connexin 43 (Cx43) has been shown to mediate GJIC in osteoblasts and it is the predominant gap junctional protein expressed in these murine osteoblast-like cells. We examined the expression, phosphorylation, and subcellular localization of Cx43 after treatment with BMP-2 or TGF-β1 to investigate a possible mechanism for the inhibition of GJIC. Results Northern blot analysis revealed no detectable change in the expression of Cx43 mRNA. Western blot analysis demonstrated no significant change in the expression of total Cx43 protein. However, significantly higher ratios of unphosphorylated vs. phosphorylated forms of Cx43 were detected after BMP-2 or TGF-β1 treatment. Immunofluorescence and cell protein fractionation revealed no detectable change in the localization of Cx43 between the cytosol and plasma membrane. Conclusions BMP-2 and TGF-β1 do not alter expression of Cx43 at the mRNA or protein level. BMP-2 and TGF-β1 may inhibit GJIC by decreasing the phosphorylated form of Cx43 in MC3T3-E1 cells.

Bone-resorbing osteoclasts are formed from hemopoietic cells of the monocyte–macrophage lineage under the control of bone-forming osteoblasts. We have cloned an osteoblast-derived factor essential for osteoclastogenesis, the receptor activator of NF-κB ligand (RANKL). Synovial fibroblasts and activated T lymphocytes from patients with rheumatoid arthritis also express RANKL, which appears to trigger bone destruction in rheumatoid arthritis as well. Recent studies have shown that T lymphocytes produce cytokines other than RANKL such as IL-17, granulocyte–macrophage colony-stimulating factor and IFN-γ, which have powerful regulatory effects on osteoclastogenesis. The possible roles of RANKL and other cytokines produced by T lymphocytes in bone destruction are described.

Large scale clinical trials demonstrate significant reductions in cardiovascular event rates with statin therapy. The observed benefit of statin therapy, however, may be larger in these trials than that expected on the basis of lipid lowering alone. Emerging evidence from both clinical trials and basic science studies suggest that statins have anti-inflammatory properties, which may additionally lead to clinical efficacy. Measurement of markers of inflammation such as high sensitivity C-reactive protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy.

Bone loss occurs when the cellular events of bone formation are quantitatively larger than bone formation. This manuscript discusses the measurement of bone loss, occurrence in the population, risk factors and consequences of bone loss. Recent developments in bone mass measurement and biomarkers have improved our ability to assess bone loss. This process is a normal concomitant of ageing. There are a number of other risk factors, including sex hormone deficiency, physical inactivity, calcium/vitamin D deficiency, inflammatory arthritis, corticosteroids, smoking and alcohol. The major consequence of bone loss in our ageing society is fracture.