Page 789 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 775

amino terminal region of PTH such that synthetic PTH 1-34 VITAMIN D
(available as teriparatide) is fully active. However, a full length
form of PTH (rhPTH 1-84, Natpara) has recently been approved Vitamin D is a secosteroid produced in the skin from 7-dehydro-
for treatment of hypoparathyroidism, as has an analog of PTHrP cholesterol under the influence of ultraviolet radiation. Vitamin
(abaloparatide). Loss of the first two amino terminal amino acids D is also found in certain foods and is used to supplement dairy
eliminates most biologic activity. products and other foods. Both the natural form (vitamin D ,
3
The metabolic clearance of intact PTH is rapid, with a cholecalciferol) and the plant-derived form (vitamin D , ergocal-
2
half-time of disappearance measured in minutes. Most of the ciferol) are present in the diet. As discussed earlier these forms dif-
clearance occurs in the liver and kidney. The inactive carboxyl fer in that ergocalciferol contains a double bond and an additional
terminal fragments produced by metabolism of the intact hor- methyl group in the side chain (Figure 42–3). Ergocalciferol and
mone have a much lower clearance, especially in renal failure. In its metabolites bind less well than cholecalciferol and its metabo-
the past, this accounted for the very high PTH values observed lites to vitamin D–binding protein (DBP), the major transport
in patients with renal failure when the hormone was measured protein of these compounds in blood, and have a somewhat dif-
by radioimmunoassays directed against the carboxyl terminal ferent path of catabolism. As a result their half-lives are shorter
region. Currently, most PTH assays differentiate between intact than those of the cholecalciferol metabolites. This influences
PTH 1-34 and large inactive fragments, so that it is possible treatment strategies, as will be discussed. However, the key steps
to more accurately evaluate biologically active PTH status in in metabolism and biologic activities of the active metabolites are
patients with renal failure. comparable, so with this exception the following comments apply
PTH regulates calcium and phosphate flux across cellular equally well to both forms of vitamin D.
membranes in bone and kidney, resulting in increased serum Vitamin D is a precursor to a number of biologically active
calcium and decreased serum phosphate (Figure 42–1). In bone, metabolites (Figure 42–3). Vitamin D is first hydroxylated in the
PTH increases the activity and number of osteoclasts, the cells liver and other tissues to form 25(OH)D, (calcifediol). As noted
responsible for bone resorption (Figure 42–2). However, this earlier there are a number of enzymes with 25-hydroxylase activity.
stimulation of osteoclasts is not a direct effect. Rather, PTH acts This metabolite is further converted in the kidney to a number of
on the osteoblast (the bone-forming cell) to induce membrane- other forms, the best studied of which are 1,25(OH) D (calcitriol)
2
bound and secreted soluble forms of a protein called RANK and 24,25-dihydroxyvitamin D (secalciferol, 24,25[OH] D), by
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ligand (RANKL). RANKL acts on osteoclasts and osteoclast pre- the enzymes CYP27B1 and CYP24A1, respectively. The regula-
cursors to increase both the numbers and activity of osteoclasts. tion of vitamin D metabolism is complex, involving calcium,
This action increases bone remodeling, a specific sequence of phosphate, and a variety of hormones, the most important of
cellular events initiated by osteoclastic bone resorption and fol- which are PTH, which stimulates, and FGF23, which inhibits
lowed by osteoblastic bone formation. Denosumab, an antibody the production of 1,25(OH) D by the kidney while recipro-
2
that inhibits the action of RANKL, has been developed for the cally inhibiting or promoting the production of 24,25(OH) D.
2
treatment of excess bone resorption in patients with osteoporosis The importance of CYP24A1, the enzyme that 24-hydroxylates
and certain cancers. PTH also inhibits the production and secre- 25(OH)D and 1,25(OH) D, is well demonstrated in chil-
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tion of sclerostin from osteocytes. Sclerostin is one of several dren lacking this enzyme who have high levels of calcium and
proteins that blocks osteoblast proliferation by inhibiting the 1,25(OH) D resulting in kidney damage from nephrocalcinosis
2
wnt pathway. Antibodies against sclerostin (eg, romosozumab) and stones. Of the natural metabolites, vitamin D, 25(OH)D
are in clinical trials for the treatment of osteoporosis. Thus, PTH (calcifediol) and 1,25(OH) D (as calcitriol) are available for
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directly and indirectly increases proliferation of osteoblasts, the clinical use (Table 42–1). A number of analogs of 1,25(OH) D
2
cells responsible for bone formation. Although both bone resorp- have been synthesized to extend the usefulness of this metabolite
tion and bone formation are enhanced by PTH, the net effect of to a variety of nonclassic conditions. Calcipotriene (calcipotriol),
excess endogenous PTH is to increase bone resorption. However, for example, is being used to treat psoriasis, a hyperproliferative
administration of exogenous PTH in low and intermittent doses skin disorder (see Chapter 61). Doxercalciferol and paricalcitol
increases bone formation without first stimulating bone resorp- are approved for the treatment of secondary hyperparathyroidism
tion. This net anabolic action may be indirect, involving other in patients with chronic kidney disease. Eldecalcitol is approved
growth factors such as insulin-like growth factor 1 (IGF1) as well in Japan for the treatment of osteoporosis. Other analogs are being
as inhibition of sclerostin as noted above. These anabolic actions investigated for the treatment of various malignancies.
have led to the approval of recombinant PTH 1-34 (teriparatide Vitamin D and its metabolites circulate in plasma tightly bound
and abaloparatide) for the treatment of osteoporosis. In the to the DBP. This α-globulin binds 25(OH)D and 24,25(OH) D
2
D production, and increases with comparable high affinity and vitamin D and 1,25(OH) D
kidney, PTH stimulates 1,25(OH) 2 2
tubular reabsorption of calcium and magnesium, but reduces with lower affinity. There is increasing evidence that it is the free
reabsorption of phosphate, amino acids, bicarbonate, sodium, or unbound forms of these metabolites that have biologic activity.
chloride, and sulfate. As mentioned earlier, full-length PTH This is of clinical importance because patients with liver disease
(rhPTH 1-84) has been approved in part for these renal effects, or nephrotic syndrome have lower levels of DBP, whereas DBP
which otherwise limit standard calcium and calcitriol treatment levels are increased with estrogen therapy and during the later
of hypoparathyroidism. stages of pregnancy. Furthermore, there are several different forms