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University of Rochester
Medical Center, Rochester, New York; and Ariad Pharmaceuticals,
Cambridge, Massachusetts, USA.
Regulation of bone remodeling and
emerging breakthrough drugs for osteoporosis and osteolytic
bone metastases. Major advances have been made in
the past 10 years in our understanding of the molecular
basis of bone cell formation and bone remodeling.
For example, the discovery of osteoprotegerin, the
decoy receptor and inhibitor of receptor activator
of NF-kappaB ligand (RANKL), and the RANKL/receptor
activator of NF-kappaB (RANK) signaling pathway that
is essential for osteoclastogenesis, has helped clarify
the mechanisms regulating osteoclast formation, activation,
and survival. PTH, like most other osteoclast stimulating
factors, promotes RANKL production by osteoblast/stromal
cells when they are exposed to it continuously, but
when given intermittently it stimulates bone formation
and reduces fracture risk in postmenopausal women.
This anabolic effect is associated with increased
expression of insulin-like and fibroblast growth factors
and decreased osteoblast apoptosis. Src tyrosine kinase
is essential for osteoclast activation and also negatively
regulates osteoblast activity. Thus, it is a well-validated
therapeutic target for the prevention of postmenopausal
and other forms of bone loss. Preliminary in vitro
and in vivo studies of specifically designed, bone
targeted, non-peptide Src inhibitors have shown that
these compounds inhibit bone resorption and stimulate
new bone formation. The design of drugs using structure/function
approaches such as this should lead to the development
of novel therapeutics that could be used to counteract
the negative effects of chronic renal failure on the
skeleton.
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Statins are widely used lipid-lowering
drugs that reduce cholesterol synthesis by inhibiting
3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase
activity. They also strongly stimulate bone formation
in rodents. If the drugs' potent bone-building activity
results directly from inhibition of HMG-CoA reductase,
there should be less bone fracturing in humans who
have taken statins to lower their serum cholesterol
and prevent heart attacks, but the data gleaned from
several databases are contradictory. According to
some reports the lipid-lowering doses of oral statins
increased bone mineral density and more than halved
the risk of fracturing various bones, while according
to others, including the very large Women's Health
Initiative Observational Study (WHI-OS), the drugs
did not significantly affect the fracturing risk.
Such contradictory data could be due in part to one
of the commonly used statins, pravastatin which only
targets hepatocytes, or due to bone growth being stimulated
by something other than inhibition of HMG-CoA reductase.
Therefore, different doses of statins may be needed
to build bone or optimally lower serum cholesterol.
To be able to answer the question posed by the title
of this editorial, it will be necessary to carry out
a controlled trial using designer statins that are
less liver-oriented and thus better for assessing
the optimal doses needed, specifically for osteogenicity
rather than for their cholesterol-lowering ability.
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