Page 801 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 787

Vitamin D, PTH,
40 Sr 2+ , anti-sclerostin

Estrogen,
Percent change in bone mineral density 20 denosumab,
calcitonin, or
bisphosphonate

0
−10 No treatment

0 1 2 3 4 5
Time (y)
FIGURE 42–5 Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the
2+
untreated condition, bone is lost during aging in both men and women. Strontium (Sr ), parathyroid hormone (PTH), and vitamin D promote
bone formation and can increase bone mineral density in subjects who respond to them throughout the period of treatment, although PTH
and vitamin D in high doses also activate bone resorption. Sclerostin antibodies, currently in clinical trials, provide a pure anabolic action in
the treatment of osteoporosis by promoting bone formation and inhibiting bone resorption. In contrast, estrogen, calcitonin, denosumab,
and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially
decreased. However, with time, both bone formation and bone resorption decrease with these pure antiresorptive agents, and bone mineral
density reaches a new plateau.

while maintaining the benefit to bone. The SERM raloxifene is Denosumab, the RANKL inhibitor, is of comparable efficacy
approved for treatment of osteoporosis. Like tamoxifen, raloxifene to bisphosphonates in the treatment of postmenopausal osteopo-
reduces the risk of breast cancer. It protects against spine fractures but rosis. It is given subcutaneously every 6 months in 60-mg doses.
not hip fractures—unlike bisphosphonates, denosumab, and teripa- Like the bisphosphonates it suppresses bone resorption and sec-
ratide, which protect against both. Raloxifene does not prevent hot ondarily bone formation. Denosumab reduces the risk of both
flushes and imposes the same increased risk of venous thromboembo- vertebral and nonvertebral fractures with comparable effectiveness
lism as estrogen. To counter the reduced intestinal calcium transport to the potent bisphosphonates.
associated with osteoporosis, vitamin D therapy is often used in com- Strontium ranelate has not been approved in the United States
bination with dietary calcium supplementation. In several large stud- for the treatment of osteoporosis but is being used in Europe,
ies, vitamin D supplementation (800 IU/d) with calcium has been generally at a dose of 2 g/d.
shown to improve bone density, reduce falls, and prevent fractures,
although calcium and vitamin D are generally used as supplements X-LINKED & AUTOSOMAL DOMINANT
with other drugs in the treatment of osteoporosis. Calcitriol and its
analog, 1α(OH)D , have also been shown to increase bone mass and HYPOPHOSPHATEMIA & RELATED
3
reduce fractures. Use of these agents for osteoporosis is not FDA- DISEASES
approved, although they are used for this purpose in other countries.
The 1,25(OH) D analog eldecalcitol is approved for use in Japan, These disorders usually manifest in childhood as rickets and hypo-
2
largely replacing the use of 1α( OH)D . phosphatemia, although they may first present in adults. In both
3
Teriparatide, the recombinant form of PTH 1-34, is approved X-linked and autosomal dominant hypophosphatemia, biologi-
for treatment of osteoporosis. It is given in a dosage of 20 mcg cally active FGF23 accumulates, leading to phosphate wasting in
subcutaneously daily. Teriparatide stimulates new bone formation, the urine and hypophosphatemia. In autosomal dominant hypo-
but unlike fluoride, this new bone appears structurally normal phosphatemia, mutations in the FGF23 gene replace an arginine
and is associated with a substantial reduction in the incidence required for proteolysis and result in increased FGF23 stability.
of fractures. The drug is approved for only 2 years of use. Trials X-linked hypophosphatemia is caused by mutations in the gene
examining the sequential use of teriparatide followed by a bisphos- encoding the PHEX protein, an endopeptidase. Initially, it was
phonate after 1 or 2 years are in progress and look promising. Use thought that FGF23 was a direct substrate for PHEX, but this no
of the drug with a bisphosphonate has not shown greater efficacy longer appears to be the case. Tumor-induced osteomalacia is a
than the bisphosphonate alone, although recent trials with the phenotypically similar but acquired syndrome in adults that results
concomitant use of teriparatide and denosumab show promise. from overexpression of FGF23 in tumor cells. The current concept
Calcitonin is approved for use in the treatment of postmeno- for all of these diseases is that FGF23 blocks the renal uptake of
pausal osteoporosis. It has been shown to increase bone mass and phosphate and blocks 1,25(OH) D production leading to rickets in
2
reduce fractures, but only in the spine. It does not appear to be as children and osteomalacia in adults. Phosphate is critical to normal
effective as bisphosphonates or teriparatide. bone mineralization; when phosphate stores are deficient, a clinical