Bone mineral homeostasis drugs Flashcards
Mineral homeostasis
Calcium and phosphate are major mineral constituents of bone
- -> principle structural support
- -> space for hematopoiesis
Principal regulators
- PTH = peptide –> single chain polypeptide produced by the PTH gland as a 115 amino acid precursor
- –> ca sensitive proteases within gland cleave to 84 amino acid active hormone
- –> gland also contains vit D receptors and enzyme that produces active vitD (CYP27B1) - vit D –> secosteroid produced in the skin from 7-dehydrocholesterol under the influence of UV radiation
- –> also found in certain foods and is used to supplement dairy products
- –> active metabolite of vit D = 1,25 dihydroxy vit D3 (calcitriol)
Secondary regulators = calcitonin, prolactin, GH, insulin, thyroid hormone, glucocorticoids, sex steroids
Mineral homeostasis
- calcitonin
Calcitonin –> secreted by parafollicular cells of the thyroid gland
- principal action is to lower serum calcium and phosphate by actions on the bone and kidney
- inhibits osteoclastic bone resorption
- ultimately both resorption and formation are inhibited –> not very useful for restoring bone mass
- due to its ability to reduce serum calcium, can be used for hypercalcemia and paget’s disease
Mineral homeostasis
- glucocorticoids
Glucocorticoids –> prolonged administration is a common cause of osteoporosis in adults and stunted skeletal development in kids
- antagonizes vit D stimulated intestinal ca transport
- stimulates renal ca excretion
- blocks bone collagen synthesis
- increases PTH stimulated bone resorption
- –> useful in reversing hypercalcemia associated with lymphomas and sarcoidosis or in case of vitD intoxication
Mineral homeostasis
- estrogens
Post menopausal bone loss
- accelerated rate of bone loss following menopause
- previously gave HRT to suppress bone loss (no longer used as it increases risk of developing breast cancer)
- estrogens reduce bone resorptive action of PTH
- estrogen receptors have been found on the bone, suggesting direct effect on bone remodeling
- lack of estrogen receptor or aromatase deficiency produces osteopenia and failure to close epiphyses
Raloxifene –> selective estrogen receptor modulator
- estrogenic actions (ER agonist) at the bone, while anti-estrogenic (ER antagonist) in the breast and uterus
- as effective as tamoxifen in reducing the risk of breast cancer
- adverse reactions –> hot flashes, blood clots, teratogenic
Bisphosphanates
Analogs of pyrophosphate –> P-O-P bond replaced by P-C-P bond
- retard formation of hydroxyapetite crystals within and outside the skeletal system; exact mechanism unclear
Mechanism of action depends on their structure
- central to their structure is a carbon to which 2 functional groups, R1 and R2, are attached
- R1 –> allows for increased binding to hydroxyapatite
- R2 –> allows for increased resorptive activity
2 classes of bisphosphanates, based on their R2 functional group
- aminobisphosphonates - contain an amino based group
- non-aminobisphosphonates - contain an alkyl group
- -> both classes inhibit bone resorption, but with different efficacies due to their different structures - modulates their ability to inhibit bone resorpotion and osteoclast formation
Bisphosphanates - Mechanism of action
Both classes bind to mineralized bone matrix and become detached following bone resorption, where they are taken up by osteoclasts
- Once internalized by the osteoclast, the two classes differ in mechanism
Non-amino bisphosphanates –> metabolized to non-hydrolysable analogues of ATP
- accumulate in the osteoclast and inhibit metabolic processes, which require ATPase pumps –> leads to apoptosis of the osteoclasts
Aminobisphosphanates –> inhibit the cholesterol biosynthesis pathway through inhibition of farnesyl pyrophosphate synthase = a key enzyme responsible for the synthesis of isoprenoids
- isoprenoids are necessary for the post-translational modification of small GTPase proteins
- GTPase protein are essential in many steps of osteoclast mediated bone resorption
- Loss of GTPase activation due to loss of isoprenoid synthesis inhibits these steps within osteoclasteogenesis, which results in loss of bone resorption
Bisphosphanates
- clinical use
- adverse effects
Clinical use –> approved for use in treatment of osteoporosis, pagets, bone mets, multiple myeloma, other skeletal related malignancies
Adverse effects
- osteonecrosis of the jaw –> occurs in 1-3% of those treated for multiple myeloma or other cancer; treated monthly, whereas in other indications for treatment only treated yearly
- atypical subtrochanteric femur fractures
RANKL inhibitor
Denosumab
- antibody against RANK ligand
- s.c. injection every 6 months
- reduced fractures by 50% in 5 year studies
- degree of anti-resorptive effect is greater than BP, but duration of osteoclast suppression is less than BPs –> 6 months after injection vs. 1 year with BPs
Mechanism
- PTH acts on the osteoblasts to induce membrane bound RANKL
- RANKL activates RANK on the surface of osteoclast precursors –> leads to maturation of osteoclasts and increase in number and activity of osteoclasts
Insurance usually won’t cover as 1st line tx
- use after failure to respond to bisphosphanate or bone loss on BP
- intolerance to BPs
- after 5 years of BP
Used in breast and prostate cancers
- preferentially metastasize to the bone
- hormonal therapy given to treat these cancers can lead to increased bone loss
Fluoride
Plicamycin
Thiazides
Fluoride
- dental carries
- fluoride alone without calcium supplement results in osteomalacia
Plicamycin
- for pagets disease and hypercalcemia
- inhibits RNA synthesis
Thiazides
- reduce renal calcium excretion
- increase effectiveness of PTH in stimulating renal calcium resorption
