Current Pharmaceutical Design, Volume 9, No. 32, 2003
Contents
Osteoporosis
Executive
Editor: Paul Morley
New Insights Into the Molecular Mechanisms
of Action of Bisphosphonates Pp.2643-2658
Michael
J.
Rogers
Calcitonin for Osteoporosis and Bone Pain Pp.2659-2676
N.M.
Mehta, A. Malootian and J.P. Gilligan
Runx2/Cbfa1: A Multifunctional Regulator
of Bone Formation Pp.2677-2685
J.B.
Lian and G.S. Stein
Dietary Intake and Bone Status with Aging Pp.2687-2704
Katherine L. Tucker
Abstracts
[Back to top] New Insights Into the Molecular Mechanisms
of Action of Bisphosphonates
Michael
J.
Rogers
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 geranylgernylated 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.
[Back to top] Calcitonin for Osteoporosis and Bone Pain
N.M.
Mehta, A. Malootian and J.P. Gilligan
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.
[Back to top] Runx2/Cbfa1: A Multifunctional Regulator
of Bone Formation
J.B. Lian and G.S. Stein
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.
[Back to top] Dietary Intake and Bone Status with Aging
Katherine L. Tucker
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.