B-28. Agents affecting bone mineral homeostatsis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.). Pharmacotherapy of osteoporosis. Flashcards
3 main hormones controling bone mineral homeostasis
- Vitamin D
- Fibroblast Growth Factor 23
- Parathryoid Hormone
What is the process of Vitamin D activation starting with the skin?
7-dehydrocholesterol → cholecalciferol via UV in skin → calcifediol via liver 25-OHation → calcitriol (1,25-OH vitamin D) via kidney 1-OHation
Vitamin D actions
-
Vitamin D actions: overall ↑ serum Ca and Pi
- ↑ Ca / Pi absorption from GI tract
- ↑ RANKL production by osteoblasts
- ↑ FGF-23 release from bone
- ↓ Ca / Pi excretion from kidney
- ↓ PTH production by parathyroid
- Immune effects: receptors on lymphocytes and APCs regulate immune function; ↓ vitamin D is assoc. with autoimmunity + ↑ infections
Fibroblast Growth Factor 23 is released from what? Actions?
Fibroblast Growth Factor 23 - released from osteocytes; overall ↓ serum Pi
-
FGF-23 actions:
- ↓ Pi reabsorption in kidney ( → ↑ excretion)
- ↓ 1-α hydroxylase in kidney → ↓ vitamin D
- Parathyroid hormone
- Overall effect
- Drug derivative
- Physiological downregulation of PTH
Parathyroid Hormone - overall ↑ Ca and ↓ Pi in serum
- an 84 AA hormone with a 34 AA active peptide (active peptide available as teriparatide drug)
- on parathyroid cells senses serum calcium level: ↑ Ca++ → ↓ PTH release
PTH mainly stimulates
- PTH stimulates:
- Osteoclast/-blast differentiation from monocytes / stem cells, respectively
- production by osteoblasts, which binds RANK on osteoclasts, activating them and thus bone resorption + subsequent remodeling by osteoblasts
- 1-α hydroxylase in kidney → ↑ vitamin D production
- Phosphate excretion in kidney
Osteoblast aslo produce what? What is it’s function? Short term PTH action leads to?
- Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL which binds and inactivates it, balancing RANKL activation of osteoclasts
- Short-term PTH action results in more OPG than RANKL action → more osteosynthesis; repeated short-term PTH → net bone mass increase
Secondary hormones in bone homeostasis
- Calcitonin
- Glucocorticoids
- Estrogens
Calcitonin function? Is it more physiologically or pharmacologically important?
- Calcitonin
- From thyroid parafollicular cells; results in ↓ serum Ca/Pi by inhibiting osteoclasts; long-term inhibition of both bone resorption + formation; less physiologically important, but can be used pharmacologically
Glucocorticoids effects? Leads to long term?
Glucocorticoids - ↓ absorption + ↑ excretion of Ca → ↓ bone formation
Long-term → osteoporosis
Estrogen effects on bones?
Estrogens- prevent post-menopausal bone loss via ↓ PTH action and ↑ calcitriol
Non-nitrogen Bisphosphonate drugs (3)
- Etidronate
- Clodronate
- Tiludronate
Nitrogen Bisphosphonate drugs (5)
- Zolendronate
- Pamidronate
- Alendronate
- Ibandronate
- Risedronate
Bisphosphonates general MOA?
Bisphosphonates: most effective inhibitors of bone resorption
- MOA: pyrophosphate (PPi) analogs → bind to bone minerals, then taken up by + inhibit osteoclasts
Non-nitrogen bisphosphonates MOA?
Nitrogen bisphosphonates MOA
- Non-nitrogen BPh: incorporate into ATP and have a cytotoxic effect
- Nitrogen BPh: inhibits farnesyl PPi synthase + thus the mevalonate pathway
Main effect of bisphosphonates lead to? Nitrogen or non-nitrogen bisphosphonates are used more often?
- Lead to ↓ bone turnover, initial ↑ bone mineral density + later stabilized bone mineral homeostasis
- Nitrogen-containing drugs (ex: alendronate) used more now than earlier non-nitrogen Bphs (ex: etidronate, the first BPh)
Indications of bisphosphonates
- Osteoporosis
- Hypercalcemia- via hyper-PTH or malignant lytic lesions
Side effects of osteoporsis
-
Side Effects:
- Upper GI effects - reflux, esophagitis w/ ulcers (w/ oral admin; prevent w/ hydration + sit upright)
- Mandibular Osteonecrosis - rare; mostly with IV admin
- Hypocalcemia- via osteoclast inhibition; transient + more with IV admin
- SERMs
- Drug name?
- MOA?
- Indication?
- SERMs - Raloxifene
- MOA: estrogen agonist in bone; antagonist in breast, uterus
- Indication: use in osteoporosis patients not tolerant to BPhs
Synthetic PTH
Teriparatide
What is the antibody used in osteoporsis?
Denosumab
- MOA: anti-RANKL monoclonal antibody
Calcimimet drug? MOA? Use?
- Cinacalcet
- Activates calcium sensing receptor (CaSR)
- In the parathryoid gland by activating CaSRs will inhibit PTH secretion
- Clinical use: secondary hyperparathyroidism (in chronic kidney disease), parathryoid carcinoma
- CaSR antagonist might be used to stimulate intermittent PTH secretion in osteoporosis
Nonhormonal agents affecting bone mineral homeostasis (4)
- Cinacalcet
- Thiazide diuretics
- Fluoride
- Strontium ranelate
Thiazide diuretics effect in bone homestsis
Thiazide diuretics - ↑ PTH-mediated Ca resorption; ↓ hypercalciuria / stones
Fluoride diuretics effect in bone homestsis
Fluoride - stabilizes hydroxyapatite; promotes bone growth + improves Ca balance (but no ↓ in fractures!)
Strontium Ranelate in bone homeostasis
Strontium Ranelate - ↓ bone resorption via osteoclast apoptosis → ↑ bone formation (EU, not US)
Calcitonin MOA and Indication
Calcitonin
- MOA: directly inhibits osteoclasts → ↓ resorption → ↓ serum Ca; also ↑ renal Ca excretion
- Indication:
- Osteoporosis- 2nd line to ↓ resorption
- Severe hypercalcemia - as in malignant lytic bone lesions
- Paget’s disease -
-
Side Effects:
- Hypocalcemia
Endogenous drug given in osteoporosis due to deficiency in most people?
Vitamin D
Osteoporosis definition
- Definition: a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture
Bone T score
- 1 SD: normal
- -1 – 2.5 SD: osteopenia
- Below -2.5 SD: osteoporosis
- Below -2.5 SD + at least one vertebral fracture: severe osteoporosis
Risk factors for osteoporosis
- Genetic factors
- Environmental factors: smoking, alcohol, physical inactivity, thin habitus, low body weight < 58kg, low calcium intake and little exposure to sun light
- Menstrual status: meonpause < 45 year, previous amenorrhea
- Drug therapy: glucocorticoids, antiepileptic drugs (phenytoin), excessive substitution therapy with thyroxine, hydrocortisone, anticoagulants, heparin, dicoumarin derivatives
- Endocrine (hyperparathyroidism, thyretoxicosis), GI (malabsorption), rheumatologic, hematologic disease
Treatment strategy of postmenopausal osteoporosis. Main point?
- The main direction of therapy is the inhibition of the increased osteoclast activity
- A substance truly stimulating bone formation did not reach yet the clinical practice
Treatment options for osteoporosis
- Hormone substitution therapy (for women)
- Selective estrogen receptor modulators (SERM) (for women)
- Denosumab
- Bisphosphonates
- Parathyroid hormone (PTH 1-34=Teriparatide)
- Vitamin D intake
- Thiazide diuretics
- Hormone substitution therapy
- What does menopause do to the bones?
- How does hormone substitution therapy work?
- What risks are increased iwth treatment?
- Hormone substitution therapy
- The menopause induces accelerated bone loss the first 4-5 years, which is followed by a linear decrease, above 75 years of age bone loss becomes accelerated again
- Hormone replacement therapy (HRT) increases BMD, decreased bone turnover and the number of bone fractures
- It is effective until administered
- Estrogen (combined with progestin if the uterus is intact) increases risk of breast cancer, may enhance the risk of cardiovascular disease
Prolonged HRT is not recommended anymore
Selective estrogen receptor modulators (SERM) drugs
- Raloxifen
- Tamoxifen
SERMs effect
- Act on the estrogen receptors
- In some organs they act as agonists, while in others as antagonists
- In the treatment of osteoporosis those SERMs have clinical importance which are
- Agonists: in the bones
- Antagonists: in the breast and uterus
Do SERMs increase the cardiovascular risk?
- SERMs do not increase the overall cardiovascular risk but increase significantly the risk of thromboembolism
Raloxifen
- Efficacy?
- Risks?
- Protects against what kind of fractures?
- Efficacy on the bones is equal to that of estrogen
- The thickness of endometrium, breast pain, vaginal bleeding, hot flushes, did not increase compared with placebo
- Imposes the same increased risk for venous thromboembolism as estrogen
- Protects against spine fractures but not hip fractures (unlike bisphosphonates, denosumab and teriparatide protect against both)
Parathyroid hormone drug? MOA?
- Teriparatide is the first 34 amino acids of the PTH
- PTH stimulates both bone resorption and bone formation
Continuous and intermittent treatment difference and similarities?
- Continuous and intermittent treatment stimulates bone formation equally, however:
- Continuous treatment leads to persistent increase of PTH level and relatively larger bone resoprtion
- Daily small doses lead to minimal bone resoprtion and substantial bone formation
- Vitamin D drugs
- Vitamin D intake
- Vitamin D3 (cholecalciferol)
- Vitamin D2 (ergocalciferol)
- Active forms of vitamin D
- a-hydroxyvitamin D3 (1a-hydroxycalciferol)
1,25-dihydroxyvitamin D3 (1,25 dihydroxycholecalciferol)
