Current Pharmaceutical Design - Volume 9, Issue 32, 2003

The present issue of “Current Pharmaceutical Design” is dedicated to osteoporosis. Osteoporosis is characterized by low bone mass and deterioration of bone leading to increased risk of fracture. It is often called the “silent epidemic” because bone loss occurs without symptoms. One in two women and one in eight men over the age of 50 has osteoporosis, and up to 200 million people worldwide are at risk of osteoporotic fracture. Current anti-resorptive treatments for osteoporosis (estrogen, calcitonin, SERMs, bisphosphonates) can only slow the progression of the disease by inhibiting boneresorbing osteoclasts. Because there are no symptoms, the disease generally goes untreated until a fracture occurs and at that stage current treatments are less effective. Osteoporosis is age-related, and because of increasing life expectancy, the World Health Organization regards osteoporosis as the world's second most important health care problem. The introduction of bone-building drugs to replace lost bone and reduce fracture incidence is one of the most significant unmet medical needs. The issue consists of four reviews. The first two reviews provide recent information on the anti-resorptive bisphosphonates and calcitonin. Dr. Michael Rogers [1] describes the molecular mechanisms by which bisphosphonates act to inhibit osteoclast-mediated bone resorption. Inhibition of a key enzyme in the mevalonate pathway, FPP synthase, can explain the loss of osteoclast bone resorptive activity and the adverse effects of bisphosphonates in the gastrointestinal tract. Drs. Mehta, Malootian and Gilligan [2] then review the actions of calcitonin to preserve bone mineral density and act as an analgesic for bone pain. Novel alternate routes of administration are being investigated to make currently approved anti-resorptive agents more patient friendly. Drs. Lian and Stein [3] review the Runx (AML /Cdfa) family of transcription factors that regulate gene expression at several points in the osteogenic lineage. Novel mechanisms related to Runx regulation of osteoblast differentiation are potential targets for therapeutic agents targeted to bone. The last review by Dr. Katherine Tucker [4], discusses modifiable dietary risk factors for osteoporosis. While the majority of published information focuses on calcium and vitamin D, there has recently been considerable interest in the effects of minerals, vitamins, macronutrients and food components on bone loss and osteoporosis. Prevention of bone loss through diet is clearly very complex and for many factors the evidence is still inconclusive. A much better understanding of the role of each of these factors and the interactions between genetics and nutrition is needed to develop effective patient guidelines for the prevention of bone loss in our aging population. I wish to thank all of the authors for their excellent contributions. References [1] Rogers MJ. New Insights Into the Molecular Mechanisms of Action of Bisphosphonates. Curr Pharm Design 2003; 9(32): 2643-2658. [2] Mehta NM, Malootian A, Gilligan JP. Calcitonin for Osteoporosis and Bone Pain. Curr Pharm Design 2003; 9(32): 2659-2676. [3] Lian JB, Stein GS. Runx2 / Cbfa1: A Multifunctional Regulator of Bone Formation. Curr Pharm Design 2003; 9(32): 2677-2685. [4] Tucker KL. Dietary Intake and Bone Status with Aging. Curr Pharm Design 2003; 9(32): 2687-2704.

Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.

Calcitonin has been approved for the treatment of osteoporosis and other diseases involving accelerated bone turnover for approximately 25 years. The most commonly studied and prescribed form is salmon calcitonin, which has a greater efficacy in clinical use. A wealth of well-controlled clinical studies have demonstrated that calcitonin preserves or increases bone mineral density (BMD) and reduces the risk of vertebral fractures in osteoporosis. Recent studies have indicated that while a low BMD is correlated with an increase in fracture risk, increases in BMD alone do not explain the antifracture efficacy of antiresorptive therapies such as calcitonin. Therapies that moderately increase BMD may reduce fracture risk by reducing the rate of bone turnover and maintaining the integrity of the trabecular architecture, resulting in the preservation of bone strength and quality in osteoporotic patients. An advantage of calcitonin that is not shared by other antiresorptive therapies is its direct analgesic effect on bone pain. Calcitonin has been demonstrated to be clinically useful in improving pain, not only from the acute vertebral fractures of osteoporosis, but also in Paget's disease, bone malignancies, and other sources of musculoskeletal pain. Drugs containing calcitonin may be approved for additional indications in the near future, and as more convenient routes of administration such as the oral route become available, the demand for the calcitonin peptide is expected to increase.

Runx2/Cbfa/AML3 is a member of the runt homology domain family of transcription factors, essential for osteoblast differentiation and bone formation. Defining the molecular mechanisms by which Runx2 can function as a master regulatory gene for activating the program of osteoblastogenesis has provided novel insights for transcriptional regulation of tissue-specific genes. Regulation of Runx expression has the potential to serve as a basis for the design of novel therapeutic strategies for promoting bone formation. Here we review the unique properties of Runx2 that mediate several key functions necessary for regulating skeletogenesis, controlling osteoblast growth and differentiation, and integrating the complex pathways required for bone formation and turnover.

Osteoporosis and related fractures represent major public health problems that are expected to increase dramatically in importance as the population ages. Dietary risk factors are particularly important, as they are modifiable. However, most of the attention to dietary risk factors for osteoporosis has focused almost exclusively on calcium and vitamin D. Recently, there has been considerable interest in the effects of a variety of other nutrients on bone status. These include minerals - magnesium, potassium, copper, zinc, silicon, sodium; vitamins - vitamin C, vitamin K, vitamin B12, vitamin A; and macronutrients - protein, fatty acids, sugars. In addition, foods and food components, including milk, fruit and vegetables, soy products, carbonated beverages, mineral water, dietary fiber, alcohol and caffeine have recently been examined. Together the evidence clearly suggests that prevention of bone loss through diet is complex and involves many nutrients and other food constituents. For many, results remain inconclusive and in some cases contradictory. However, it is increasingly clear that our exposure to a complex of nutrients and food constituents interacts to affect bone status. In addition to identifying the role of individual components, there is a great need to understand the interactions of these factors within diets and, increasingly, in the presence of nutrient supplements. Furthermore, genetic factors are likely to interact with these dietary exposures, increasing the complexity of these effects. With advances in both genetics and nutrition, improved understanding of all these interactions will contribute to effective recommendations for prevention of bone loss and osteoporosis in the aging population.