Summary
Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.

Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy

Bisphosphonates: The first 40 years

Systemic corticosteroids play an integral role in the management of many inflammatory and immunologic conditions, but these agents are also associated with serious risks. Osteoporosis, adrenal suppression, hyperglycemia, dyslipidemia, cardiovascular disease, Cushing’s syndrome, psychiatric disturbances and immunosuppression are among the more serious side effects noted with systemic corticosteroid therapy, particularly when used at high doses for prolonged periods. This comprehensive article reviews these adverse events and provides practical recommendations for their prevention and management based on both current literature and the clinical experience of the authors.

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A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy

This article reviews the risks of osteoporosis and osteonecrosis associated with glucocorticoid use, which are present even in the absence of low bone mineral density, and discusses strategies to reduce the risk of fractures and the data to support the strategies.

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Glucocorticoid-Induced Bone Disease

The etiology of osteonecrosis of the hip may have a genetic basis. The interaction between certain risk factors and a genetic predisposition may determine whether this disease will develop in a particular individual.The rationale for use of joint-sparing procedures in the treatment of this disease i

Nontraumatic osteonecrosis of the femoral head: ten years later.

Background: Osteonecrosis of the femoral head is the most common diagnosis leading to total hip arthroplasty in young adults. Joint-preserving treatment options have been mainly surgical, with inconsistent results. Alendronate (a bisphosphonate agent) has been shown to lower the prevalence of vertebral compression fractures and could potentially retard the collapse of an osteonecrotic femoral head. The purpose of this study was to test the effect of alendronate in preventing early collapse of the femoral head in patients with nontraumatic osteonecrosis.

Methods: Forty patients with Steinberg stage-II or III nontraumatic osteonecrosis of the femoral head and a necrotic area of >30% (class C) were randomly divided into alendronate and control groups of twenty patients each. Patients in the alendronate group took 70 mg of alendronate orally per week for twenty-five weeks, while the patients in the control group did not receive this medication or a placebo. The patients were observed for a minimum of twenty-four months. Harris hip scores, plain radiographs, and magnetic resonance imaging scans were obtained.

Results: During the study period, only two of twenty-nine femoral heads in the alendronate group collapsed, whereas nineteen of twenty-five femoral heads in the control group collapsed (p < 0.001). One hip in the alendronate group underwent total hip arthroplasty, whereas sixteen hips in the control group underwent total hip arthroplasty (p < 0.001).

Conclusions: Alendronate appeared to prevent early collapse of the femoral head in the hips with Steinberg stage-II or IIIC nontraumatic osteonecrosis. A longer duration of follow-up is needed to confirm whether alendronate prevents or only retards collapse.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study.

Study design Case control study. Objective To investigate the histopathologic findings of 2 retrieved specimens from failed vertebroplasty with polymethylmethacrylate (PMMA) cement. Summary of background data Vertebroplasty using PMMA cement has been commonly used to treat debilitating back pain from compression fracture, angiomas, and metastatic cancer. However, there was concern about the unpredictable future results with PMMA cement. The histopathologic changes were rarely reported. Methods There were 2 PMMA augmented and 3 nonaugmented fractured vertebral bodies retrieved for histopathologic study. Between the 2 groups, we compared the findings of bone necrosis, foreign body reaction, fibrotic wall formation, and neovascularization. Results Bone necrosis was noted in the periphery of PMMA cement, which was surrounded by fibrotic tissues. In contrast, no fibrotic wall formation could be found in the nonaugmented control group. Foreign body reaction was only noted in PMMA augmented cases, and neovascularization was only noted in the control cases. Conclusion PMMA cement might not be as bioinert as we considered. Therefore, the long-term safety of vertebroplasty should be further evaluated.

Histopathologic findings of retrieved specimens of vertebroplasty with polymethylmethacrylate cement: case control study.

STUDY DESIGN Prospective analysis. OBJECTIVE To investigate biologic influences of recombinant human bone morphogenetic protein (rhBMP)-2 on intervertebral discs after anular tears. SUMMARY OF BACKGROUND DATA Treatments for intervertebral disc injury or degeneration are unsatisfactory. rhBMP-2, a high-potency osteoinductive and chondroinductive substance, is approved for use in anterior lumbar interbody fusions. rhBMP-2 stimulates the proliferation of rat disc cells and the secretion of extracellular matrix in vitro. In vivo responses in the intervertebral disc after anular tears are rarely studied. METHODS Twenty New Zealand white rabbits received full-thickness anular tears and intradiscal injections of saline (control) and rhBMP-2 0.1 mg with and without coral grafts at L2-L3, L3-L4, and L4-L5, respectively. Three died or had infection. Therefore, 17 underwent radiography and sacrifice at 12 weeks. Spinal sections were stained with hematoxylin and eosin to examine responses to rhBMP-2. RESULTS Radiographs revealed degenerative changes, such as disc space narrowing and irregularity, subchondral sclerosis, osteophyte formation, and hypertrophy of vertebral endplates in all groups. Degeneration was more frequent and severe with rhBMP-2 with (P < 0.01) and without (P < 0.05) coral than with saline. Two rabbits receiving rhBMP-2 and coral achieved solid interbody bony fusion. New bone formation was noted in 2 controls, in 3 animals treated with rhBMP-2, and in 4 treated with rhBMP-2 and coral. Vascularity and fibroblast proliferation increased with rhBMP-2 (n = 14) and rhBMP-2 with coral (n = 9) compared with control (n = 3; P < 0.01 and P = 0.03, respectively). Inflammatory infiltrates increased with rhBMP-2 (n = 8) compared with control (n = 2; P = 0.03). CONCLUSIONS Degenerative changes were more frequent and severe in the groups treated with rhBMP-2 with or without coral in radiographic findings. In histopathologic findings, rhBMP-2 promoted hypervascularity and fibroblast proliferation of the intervertebral disc after an anular tear.

The in vivo biological effects of intradiscal recombinant human bone morphogenetic protein-2 on the injured intervertebral disc: an animal experiment.

Study design The gene expression of interleukin (IL)-20 on human herniated intervertebral disc. OBJECTIVE.: To elucidate the role of novel cytokine IL-20 in the pathogenesis of human intervertebral disc (IVD) herniation. Summary of background data IL-20 is involved in inflammatory diseases such as psoriasis, atherosclerosis, and rheumatoid arthritis, etc. However, IL-20 is never reported to be associated with the pathogenesis of human disc herniation. Methods Twenty consecutive patients who were diagnosed with IVD herniation and received open discectomy were included in this study. The retrieved disc material specimens and the isolated primarily cultured disc cells were immunohistochemically stained to detect the expression of IL-20 and its receptor subunits (IL-20R1, IL-20R2, and IL-22R1). Besides, to investigate the in vitro response of IL-20 on human herniated intervertebral disc, we analyzed the effects of IL-20 alone, in combination with IL-1beta, and IL-1beta alone on the gene expression and protein levels of various cytokines, chemokines, matrix metalloproteinases (MMPs), etc. Results IL-20 and its receptors were detectable in human herniated disc tissues and isolated disc cells. In vitro, IL-1beta induced the expression of IL-20. Furthermore, IL-20 induced transcripts of IL-1beta, IL-6, vascular endothelial growth factor (VEGF), MMP-3, and monocyte chemoattractant protein (MCP-1) on primarily cultured human disc cells. IL-1beta induced transcripts of IL-1beta, IL-6, IL-8, VEGF, MMP3, and MCP-1. IL-20 combined with IL-1beta induced transcripts of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-8, MMP-3, and MCP-1 to a level higher than those found in cells treated with IL-20 or IL-1beta alone.Enzyme-linked immunosorbent assay, analysis also showed that IL-20 combined with IL-1beta up-regulated the secretion of TNF-alpha, IL-6, IL-8, and MCP-1. Conclusion IL-20 induces proinflammatory, chemotaxtic, and matrix degradative responses in IVD cells especially in combination with IL-1beta. Our study suggests that IL-20 plays an important role in the pathogenesis of disc herniation.

IL-20 may contribute to the pathogenesis of human intervertebral disc herniation.

The geometric changes of acute thoracolumbar burst fractures under extension and traction loadings were analyzed using functional radiographs. The injuries were produced in an in vitro high-speed impact model. The changes in nine geometric parameters (three angular and six linear) were analyzed from neutral posture to extension and traction positions. In the extended position, all parameters, except the posterior vertebral height and vertebral diameter, were significantly different from the neutral posture values. Also in extension, the posterior vertebral height, vertebral diameter, and posterior unit height were significantly different from their intact values. In the traction position, all nine geometric parameters changed significantly from the neutral posture, whereas only the vertebral diameter remained significantly different from its intact value. These findings demonstrated the treatment advantages of applying traction force to acute burst fractures in contrast to extension moments. Further, changes in the angular parameters due to motion from neutral to extension posture demonstrated that the acute flexibility of the three-vertebrae segment was contributed almost equally by the upper disc (35%), lower disc (27%), and fractured vertebra (38%).

Ruey Mo Lin

Papers

The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study.

Histopathologic findings of retrieved specimens of vertebroplasty with polymethylmethacrylate cement: case control study.

The in vivo biological effects of intradiscal recombinant human bone morphogenetic protein-2 on the injured intervertebral disc: an animal experiment.

IL-20 may contribute to the pathogenesis of human intervertebral disc herniation.

Functional Radiographs of Acute Thoracolumbar Burst Fractures: A Biomechanical Study