section
37.1
Calcium and Phosphorus
889
TABLE 37-3
Biochemical Markers o f Bone Formation and Bone Resorption
Markers of Bone Formation (measured in serum)
1. B on e-sp ecific alkaline phosphatase: R ich in osteoblasts
2. O steocalcin: M ajor noncollagen protein o f bone matrix
3. A m ino- and carboxyl-term inal Procollagen 1 extension peptides:
By-product o f collagen biosynthesis
Markers of Bone Resorption
Serum marker
B on e sp ecific acid phosphatase: A lysosom al en zym e o f osteoclasts
Urine Markers: A ll o f these are collagen breakdown products
1. N -T elopeptide and C -T elopeptide
2. Pyridinium cross-links (pyridinoline and deoxypyridinoline):
Posttranslational m odification o f lysine and hydroxylysine
residues o f collagen
3. H ydroxlysine glycosid es
4. H ydroxyproline
is greater than bone form ation. R ecent research indicates
that peak bone m ass, skeletal structure, and m etabolic
activity are determ ined by a large num ber o f different
gen es interacting w ith environm ental factors; thus, o s-
teoporosis is a polygenic-m ultifactorial disease. C andi-
date gen es that m ay play a role in the developm ent o f
osteoporosis include vitam in D receptor, estrogen recep-
tor, transform ing growth factor
fi,
interleukin-6, colla-
gen type 1 gen es, and collagenase. G ene knockout m ice
are used in assessin g the contribution o f various genes
to bone form ation and bone resorption. K nockout o f the
hem opoietic transcription factor PU -1 in m ice results in
the phenotype o f osteoporosis; these m ice are character-
ized by d efective osteoclast form ation and deficiency o f
m acrophages. K nockout o f the m yeloid growth factor (M -
C SF) gene produces a sim ilar phenotype. H ow ever, knock-
out o f the transcription factor c
-fos
gene causes osteopet-
rosis w ith normal m acrophage synthesis w hile knockout
o f the transcription factor
c-src
allow s form ation o f o s-
teoclasts that are unable to resorb bone norm ally. D efi-
cien cies o f other m olecules, such as cathepsin K, carbonic
anhydrase II, and tartrate-resistant acid phosphatase, also
im pair the ability o f mature osteoclasts to resorb bone.
It is apparent that many factors influence developm ent o f
osteoporosis.
O steoporosis is a com m on diagnosis in postm enopausal
w om en. M enopause results from the perm anent cessa-
tion o f ovarian function that usually precedes the final
m enses by several years and is diagnosed after 12 m onths
o f amenorrhea. M enopause and osteoporosis are causally
related based on (a) the higher rates o f osteoporotic
fractures in postm enopausal w om en; (b) loss o f bone
m ineral density in postm enopausal w om en; and (3) preser-
vation o f bone m ineral density
as
a result o f hor-
m one replacem ent therapy. M ost studies o f horm one
replacem ent therapy involving estrogen or estrogen plus
progestagen show ed increases in bone m ineral density o f
1-4% in postm enopausal w om en. A lthough the increase in
bone density is sm all, significant reduction in fractures is
reported for w om en using horm one replacem ent therapy.
Estrogen or other drugs are used to prevent osteoporo-
sis in postm enopausal w om en. B isphosphonates and cal-
citonin act as antiresorptive drugs. A ctually, these drugs
decrease the rates o f both bone resorption and bone for-
m ation, but they affect the rem odeling cy cle so that there
is a net increase in bone m ineral density o f 5-10% . Both
etidronate and alendronate (bisphosphonates, Figure 37-6)
are
used
in
the
treatment
o f osteoporosis
in
post-
m enopausal w om en and provide a treatment option if es-
trogen replacem ent therapy is contraindicated. It is thought
that bisphosphonates are incorporated into bone matrix
and incapacitate osteoclasts upon entry during resorption.
Prom otion o f osteoclast apoptosis through inhibition o f the
m evalonate-cholesterol biosynthetic pathway, w hich leads
to loss o f G-protein prénylation, is also a p ossib le m echa-
nism o f action. The use o f H M G -C oA reductase inhibitors
(statins), w hich also inhibits G -protein prénylation, d e-
creases the risk o f fractures in the elderly (discussed ear-
lier). Statins, independent o f their lipid-low ering activity,
can im prove endothelial function including the form ation
