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chapter 37
Mineral Metabolism
Both osteoblasts and osteoclasts are derived from osteo-
progenitor cells originating in the bone marrow. O steoblast
precursors are pluripotent m esenchym al stem cells and
the osteoclast precursors are hem atopoietic cells o f the
m onocyte-m acrophage lineage. The developm ent o f o s-
teoblasts and osteoclasts is regulated by several growth
factors and cytokines w h ose responsiveness in turn is m od-
ulated by system ic horm ones.
Bone morphogenetic proteins
(B M P s) are signaling
m olecules involved in the form ation o f bone and also
govern other developm ental functions. T hese proteins
belong to the transform ing growth factor
/1
superfam -
ily. B M Ps regulate m any steps in the form ation o f new
bone, such as m obilization o f progenitor cells and their
differentiation and proliferation into chondrocytes and
osteoblasts. Thus, B M Ps have therapeutic im plications
in the enhancem ent o f osteoblast differentiation and
bone form ation. For exam ple,
in vitro
and rodent stud-
ies have show n that one particular B M P (B M P -2) pro-
m otes bone form ation. H M G -C oA reductase inhibitors
that decrease hepatic cholesterol biosynthesis also acti-
vate the prom oter o f the B M P -2 gene, thereby prom ot-
ing new -bone form ation. H M G -C oA reductase inhibitors
(statins) cause decreased prénylation o f proteins, such as
G TP-binding proteins, and induction o f osteoclast apop-
tosis. (For a discussion on m evalonate-cholesterol m ulti-
functional pathway and H M G -C oA reductase inhibitors,
see Chapters 19 and 20, respectively.) Population-based,
case-controled ep id em iologic studies have shown that the
statin used by elderly individuals is associated with a d e-
creased risk o f bone fractures (e.g., hip fracture). Som e
bisphosphonates that are used clinically as potent an-
tiresorptive agents m ay also affect prénylation o f pro-
teins by inhibiting en zym es in the m evalonate-cholesterol
biosynthetic pathway
m ore distal
to the H M G -C oA
reductase catalyzed step (e.g., farnesyl-pyrophosphate
synthase).
T he transformation o f precursor cells to osteoclasts
is stim ulated by parathyroid horm one (PTH ), thyroxine,
growth horm one, and vitam in D m etabolites, whereas
calcitonin, estrogens, and glucocorticoids inhibit the for-
m ation o f osteoclasts. O steoblast form ation is prom oted
by calcitonin, estrogen, growth horm one, inorganic phos-
phate, and m echanical stress, and is antagonized by PTH
and vitam in D m etabolites. The actions o f som e o f these
agents are m ediated by cAM P.
Calcium and Phosphate Homeostasis
Four primary factors influencing calcium and phosphate
hom eostasis are diet, vitam in D and its m etabolites, PTH,
and calcitonin. Table 37-1 lists other horm ones know n to
affect hom eostasis o f these elem ents by interacting with
on e or m ore o f these factors.
Calcium and Phosphate in the Diet
Sufficient dietary calcium arid phosphate m ust be ab-
sorbed to support grow th (including pregnancy) and re-
place m ineral lost from the body. Phosphates are present
in adequate quantities in a w ide variety o f foods, and it
is very unlikely that hypophosphatem ia results from in-
adequate dietary phosphorus. Phosphate is absorbed from
the sm all intestine w ith Ca2+ as a counterion and by an
independent process that requires vitam in D m etabolites.
N orm al daily intake o f phosphate is about 8 0 0 -1 5 0 0 mg.
Phosphate is highly conserved by the body, and obligatory
lo sses are m inim al.
C alcium hom eostasis is profoundly dependent on diet
and intestinal absorption.
Rickets
and postm enopausal
osteoporosis
are related to inadequate intestinal absorp-
tion o f calcium . In the adult, an unavoidable loss o f about
3 0 0 m g o f Ca2+ per day occurs in urine, feces, and sweat.
S ince only about 30-40% o f dietary calcium is absorbed,
the recom m ended daily allow ance for adults is 800 m g o f
Ca2+ per day. A llow an ces for other age groups are shown
in Table 37-2. T hese allow ances take into account rates
o f skeletal calcium deposition o f 8 0 -1 5 0 m g/d betw een
birth and
1 0
years o f age, and o f
2 0 0
m g/d (fem ale) and
2 7 0 m g/d (m ale) during the pubertal growth period. W ith
cessation o f growth, accum ulation o f calcium normally
ceases, although bone rem odeling continues. During preg-
nancy and lactation, there is calcium deposition in the fetus
and calcium loss in m ilk. About 80% o f the 25 g o f cal-
cium present in a full-term fetus is deposited during the last
trim ester o f pregnancy. Human breast m ilk contains 30 m g
o f Ca2+ per deciliter (7.5 m m ol/L), and about 250 m g o f
calcium per day is lost in m ilk during lactation. Increased
calcium intake is recom m ended for older w om en because
TABLE 37-2
Recommended Daily Allowances o f Dietary Calcium
Group
Recommended
Daily Allowance
(RDA) (mg Ca2+)
Infants
3 6 0 -5 4 0
Children
800
Teenagers (pubertal growth period)
1 2 0 0
Adults
800
Pregnancy and lactation
1 2 0 0
W om en over 40 years old
1 2 0 0
(both pre- and postm enopausal)
