890
chapter
37
Mineral Metabolism
H O ,
R
O
I
N a O
P - C - P
/
I
'
OH
OH
ONa
B is p h o s p h o n a te
R =
C H 3 in E tid ro n a te
/ = N
R = — C H 2
in R is e d r o n a te
R = — (C H 2)3 — N H 2 in A le n d ro n a te
F I G U R E 3 7 - 6
Structures of bisphosphonates. These antiresorptive therapeutic agents are
characterized by a geminal bisphosphonate bond.
o f new blood vessels (angiogenesis). T he m echanism o f
action involves increased form ation o f nitric oxid e and ni-
tric oxid e dependent pathways. T hese pathways are linked
to the activation o f A kt-protooncogene/protein kinase m e-
diated cellular processes.
C alcitonin therapy results in decreased bone resorp-
tion. O steoclasts have calcitonin receptors and calcitonin
inhibits their activity. Sodium fluoride stim ulates bone
form ation by unknown m echanism s. In w om en with o s-
teoporosis, fluoride therapy produced an increased bone
m ineral density but no reduction in the rate o f vertebral
fractures. Other drugs known as selective estrogen re-
ceptor m odulators (raloxifene, droloxifene, idoxifene, and
levorm eloxifene) m ay provide an alternative to estrogen
replacem ent therapy (Chapter 34). Adm inistration o f low
d oses o f PTH [or recom binant PTH( 1 -3 4 )] does not affect
serum calcium concentration, prom otes bone form ation,
and increases mineral density. This anabolic action o f PTH
is probably m ediated by decreasing osteoblast apoptosis.
Osteogenesis imperfecta,
perhaps the m ost com m on
hereditary d isease o f bone, is due to a defect in collagen
form ation (Chapter 25).
Osteopetrosis
(m arble bone disease) is marked by the
form ation o f abnorm ally dense and condensed bone. It
is a genetically, biochem ically, and clinically heteroge-
neous disease. However, the underlying m echanism for
the various types o f osteopetrosis is a failure in bone re-
sorption due to defects in osteoclasts. In som e form s o f
osteopetrosis, providing normal osteoclastic precursors by
bone marrow transplantation has yielded clinical im prove-
m ent. Stim ulation o f osteoclast form ation or activity with
1,25-(O H )2D or recom binant interferon-y also has yielded
m odest clinical im provem ent.
O ne form o f osteopetrosis is caused by a deficiency o f
one o f the isoenzym es o f carbonic anhydrase (carbonic
anhydrase II). This is an autosom al recessive disorder and
four different m utations in the structural gen e o f carbonic
anhydrase II have been identified. A s discussed earlier,
the acidic environm ent necessary for resorption is gener-
ated by the action o f carbonic anhydrase II. T he patients
w ith carbonic anhydrase II d eficiency also exhibit renal
tubular acidosis and cerebral calcification. T he cause o f
renal tubular acidosis is due to failure o f reclam ation o f
bicarbonate from the glom erular filtrate because o f the
deficiency o f carbonic anhydrase in the renal tubular cells
(see Chapter 39 for the role o f carbonic anhydrase in the
reclam ation o f filtered bicarbonate in the kidney).
Three gen es coding for isoenzym es o f carbonic anhy-
drase I, II, and III, all b elonging to the sam e gene fam -
ily, are clustered on chrom osom e 8q22. T hese are all zinc
m etalloenzym es, soluble, m onom eric, and have m olecu-
lar w eights o f 29,000. Isoenzym e I is found primarily in
erythrocytes (Chapters 1 and 39) and III in skeletal m us-
cle. There are yet other isoenzym es coded for by different
genes.
Hyperphosphatemia,
often seen in renal failure, pro-
duces no specific signs or sym ptom s. In contrast, chronic
hypophosphatemia
can produce w eakness, bone pain,
congestive cardiom yopathy,
d izziness,
and
hem olytic
anem ia.
Severe hypophosphatem ia is potentially fatal and is usu-
ally due to hyperphosphaturia, shifting o f phosphate from
extracellular to intracellular fluid (as in electrolyte and
pH im balances), or dim inished intestinal absorption o f
phosphate. Iatrogenic hypophosphatem ia m ay occur in di-
abetic ketoacidosis. The im m ediate goals o f therapy are
to norm alize glu cose m etabolism and to restore fluid and
electrolyte balance. Since m etabolism o f glu cose requires
phosphate, rapid entry o f glu cose into insulin-dependent
tissues as a result o f insulin therapy shifts phosphate to
the intracellular fluid. This effect can be exacerbated by
intravenous rehydration with phosphate-poor fluids. R e-
hydration and hyperalim entation o f alcoholics (w ho are
often phosphate depleted due to poor diet, diarrhea, and
vom iting) can lead to hypophosphatem ia. Concurrent hy-
pom agnesem ia can increase phosphaturia.
37.2 Magnesium
M agnesium is the fourth m ost abundant cation in the
body after sodium , potassium , and calcium , and is the
second m ost abundant cation in intracellular fluid after
K + M g2+ is needed in m any enzym atic reactions, particu-
larly those in w hich ATP4 - • M g2+ is a substrate. M agne-
sium binds to other nucleotide phosphates and to nucleic
acids and is required for D N A replication, transcription,
and translation. The D N A h elix is stabilized by binding
