15. Agents affecting bone mineral homeostasis (calcium, vitamin D, parathyroid hormone, calcitonin, etc.). Pharmacotherapy of osteoporosis. Flashcards
primary hormonal modulators
parathyroid hormone (PTH) - Teriparatide
- kidney: Ca2+ excretion–, Phosphate excretion++, synthesis of Vit-D (stimulates renal 1alpha-hydroxylase)
- osteoblast and -clast are activated:
1. continious high stimulation -> net bone resorption
2. intermittend low concentration: net bone formation - Intestine: Ca2+ and Phosphate absorption++, (indirect by Vit D)
VitD2 (ergocalciferol)+ VitD3 (Cholecaciferol) = liver and kidney = calcitriol (1,25-dihydroxy-VitD)
- kidney: Ca2+ and Phosphate reabsorption++
- Bone: direct bone reabsorption++ Ca2+ and Phosphate, indirect effect is mineralisation by ++Ca2+ and ++Phosphate
Intestine: Absorption of Ca2+ and Phosphate
- inhibits PTH release
- Intestine and bone effect are more potent than kidney
-(Ergocalciferol,) Cholecalciferol, (Doxercalciferol) -> Prodrug
- calcitriol
(-Paricalcitol)
(-Calcipotriene)- topical
Analogues of primary hormonal modulators
parathyroid hormone (PTH) - Teriparatide
VitD2 (ergocalciferol)+ VitD3 (Cholecaciferol) = liver and kidney = calcitriol (1,25-dihydroxy-VitD)
-(Ergocalciferol,) Cholecalciferol, (Doxercalciferol) -> Prodrug
- calcitriol
(-Paricalcitol)
(-Calcipotriene)- topical
secondary hormonal modulator
Calcitonin: (calcitonin as medication itself?)
- kidney: Ca2+ and Phosphate excretion++
- bone: inhibits osteoclast activity (bone reabsorption– )
- NET: Ca2+ – (loss)
Estrogens:
- Inhibition of PTH induced bone reabsorption
- inhibits osteoclast activity
- SERM as medication: RALOXFEN
Glucocorticoids:
- intestinal and renal Ca2+ reabsorption– (down)
- RANK-Receptor suppression
- RANKL stimulation
- inhibitory effect on osteoblast and collagen synthesis
Non-hormonal modulators
Bisphosphonates:
- direct suppression of Osteoclast (fornesyl pyrophosphonate synthase)
- BMU– ??
- Ca2+ – ??
1. Alendronate!!
2. Zoledronate!!
RANK-Ligand inhibitor :
- RANK-L also plays a role in the immune response
- Denosumab!!
Calcimimetics:
- activating Ca+-sensing receptors in Parathyroid gland
(- Cinacalcet)
(Flouride: )
- stabilizes hydroxy-apatide crystals
(strontium ranelate)
- promotes osteoclast apoptosis and osteoblast activity ++
Thiazide diuretic:
- increases ca2+ level
- Hydrochlorothiazid
Parathyroid hormone (PTH)
- Kidney: Ca2+ excretion ↓, P excretion ↑, synthesis of active vitamin D (PTH stimulates renal 1α-hydroxylase enzyme)
- Bone: (both osteoclast and osteoblast are stimulated) continuous high concentration → net bone resorption; intermittent low concentration → net bone formation
- Intestine: Ca2+ and P absorption ↑ (indirect effect, mediated by vitamin D)
- Net effect on serum levels: Ca2+ ↑, P ↓
analogue:
Teriparatide
Teriparatide
Parathyroid hormone (PTH)-analogue
- Kidney: Ca2+ excretion ↓, P excretion ↑, synthesis of active vitamin D (PTH stimulates renal 1α-hydroxylase enzyme)
- Bone: (both osteoclast and osteoblast are stimulated) continuous high concentration → net bone resorption; intermittent low concentration → net bone formation
- Intestine: Ca2+ and P absorption ↑ (indirect effect, mediated by vitamin D)
- Net effect on serum levels: Ca2+ ↑, P ↓
Teriparatide
- PTH analogue (recombinant form; consists of N-terminus – 34 amino acids of parathyroid hormone)
- Subcutaneous injection
- Osteoporosis (promotes bone formation in low, intermittent doses)
- Side effects: hypercalcemia, hypercalciuria
Vitamin D
Vitamin D2 (ergocalciferol) + vitamin D3 (cholecalciferol) from skin and/or intestinal absorption → converted by the liver and kidney to the biologically active metabolite calcitriol (1,25 dihydroxy-vitamin D)
- Kidney: Ca2+ and P reabsorption ↑; urinary Ca2+ may be elevated as the effects of vitamin D are more potent on bone and GI
- Bone: direct effect is bone resorption (↑ of serum Ca2+ and P); indirect effect is promoting mineralization by increasing the availability of Ca2+ and P
- Intestine: Ca2+ and P absorption ↑
- Inhibitory effect on PTH release
- Net effect on serum levels: Ca2+ ↑, P ↑
- Vitamin D cannot be used to treat primary hyperparathyroidism; only the secondary form! For primary disease → surgical and bisphosphonate
Ergocalciferol (vitamin D2)
Cholecalciferol (vitamin D3)
Vitamin D2 (ergocalciferol) + vitamin D3 (cholecalciferol) from skin and/or intestinal absorption → converted by the liver and kidney to the biologically active metabolite calcitriol (1,25 dihydroxy-vitamin D)
- Kidney: Ca2+ and P reabsorption ↑; urinary Ca2+ may be elevated as the effects of vitamin D are more potent on bone and GI
- Bone: direct effect is bone resorption (↑ of serum Ca2+ and P); indirect effect is promoting mineralization by increasing the availability of Ca2+ and P
- Intestine: Ca2+ and P absorption ↑
- Inhibitory effect on PTH release
- Net effect on serum levels: Ca2+ ↑, P ↑
- Oral
- Require metabolism in liver and/or kidney to active forms
- Vitamin D deficiency – rickets disease, osteomalacia (nutritional deficiency, intestinal osteodystrophy, hypoparathyroidism, nephrotic syndrome)
- Side effects: hypercalcemia, hyperphosphatemia, hypercalciuria
Calcitriol
1,25 dihydroxy-vitamin D
- Oral
- Drug in active form, does not require metabolism
- Secondary hyperparathyroidism in patients with
chronic kidney disease → vitamin D inhibits PTH release, corrects hypocalcemia, and improves bone disease - Management of hypocalcemia in patients with hypoparathyroidism
- Vitamin D cannot be used to treat primary hyperparathyroidism; only the secondary form! For primary disease → surgical and bisphosphonate
Doxercalciferol
not on the list
- Analogue of calcitriol
- Prodrug
- Oral or parenteral
- Secondary hyperparathyroidism in patients with chronic kidney disease
- Side effects are milder compared to calcitriol
Paricalcitol
not on the list
Paricalcitol
- Analogue of calcitriol
- Oral
- Secondary hyperparathyroidism in patients with chronic kidney disease
- Side effects are milder compared to calcitriol
Calcipotriene (Calcipotriol)
not on the list
- Analogue of calcitriol
- Topical
- Psoriasis (vitamin D inhibits keratinocyte proliferation)
Calcitonin
Kidney: Ca2+ and P excretion ↑
- Bone: inhibits osteoclast activity (bone resorption ↓)
- Net effect on serum levels: Ca2+ ↓
- Analogue of biological source
- Subcutaneous injection, nasal spray
- Osteoporosis
- Paget’s disease
- Acute management of hypercalcemia
- Side effects:
rhinitis with the nasal spray,
hypocalcemia
Raloxifene
Estrogens
- Inhibition of PTH-induced bone resorption (inhibit osteoclast activity)
- Oral
SERM – Selective estrogen receptor modulators
- Estrogen antagonist activity → breast, CNS, uterus
- Estrogen agonist activity → liver, bone
- Osteoporosis in post-menopausal women
- Side effects: hot flushes, increased risk of venous
thromboembolism
Glucocorticoids
- Intestinal and renal Ca2+ absorption ↓
- RANK-L stimulation, RANK receptor suppression
- Inhibitory effects on osteoblast activity and collagen synthesis
Net effect → risk of osteoporosis if systemic therapy is used for prolonged time
Alendronate
Zoledronate
(Risedronate)
Bisphosphonates
- Direct suppression of osteoclast activity (inhibit farnesyl pyrophosphate synthase enzyme, which plays a critical role in osteoclast survival) → prevent bone
turnover by decreasing the number of the basic multicellular (remodelling) units - BMU
- Result in rapid increase of bone mineral density in the first year; later, a new equilibrium between bone metabolism and resorption is established
- Oral or parenteral administration
(oral bioavailability < 10%; absorption further impaired by food) - Eliminated by the kidneys with no prior metabolism
- Effect may persist for up to 2 years following treatment cessation
- Osteoporosis (1st line treatment → cost, efficacy, long- term beneficial effects)
- Paget’s disease
- Bone metastasis
- Hypercalcemia due to hyperparathyroidism
Side effects:
- hypocalcemia,
- upper GI irritation
(may be prevented by administration with large quantities of water, and avoidance of gastric reflex),
- osteonecrosis of the jaw (rare, more likely with IV use)
*Bisphosphonate is used as the carrier molecule for radio-active isotope (99mTc) during bone scintigraphy, binding hydroxyapatite in areas on increased bone turnover
Denosumab
RANK-Ligand inhibitors
RANK-L stimulates osteoclast differentiation and function → bone resorption
- Human monoclonal antibody (IgG)
- Subcutaneous injection, every 6 months
- Post-menopausal osteoporosis
- Side effects:
increased risk of infection
(role of RANK-L in the immune response)
Cinacalcet
not on the list
Calcimimetics
Lowers PTH levels by activating the Ca2+-sensing receptor in the parathyroid gland
- Oral
- Secondary hyperparathyroidism due to chronic kidney disease
- Management of parathyroid carcinoma
- Side effects: nausea, hypocalcemia, adynamic bone
disease (decreased bone activity)
Fluoride
not on the list
- Accumulates in bones and teeth, stabilizes the hydroxyapatite crystals
- Promotes new bone growth
Fluoride - Oral or in drinking water and toothpaste
- Effect is doubtful
- Side effect (acute toxicity): GI and neurological
symptoms
Strontium ranelate
not on the list
- Promotes osteoclast apoptosis, enhances osteoblast activity
- Not in clinical use due to financial reasons
- Osteoporosis
Thiazide diuretics
- Increases Ca2+ serum level
- Osteoporosis
Inhibit Na+/Cl- transporter in distal convoluted tubule
Hydrochlorothiazide
- Oral
- Duration of action 8-12 h’
- Hypertension
- Congestive heart failure
- Mild edema
- Sulfonamide derivative
Drug interactions
- Digoxin (enhanced toxicity due to electrolyte disturbances)
- Avoid in patients with diabetes mellitus
Inhibition of Na+/Cl- transporter (NCC) in the distal convoluted tubule
- Natriuresis (loss of NaCl) – effect is moderate but sustained
- Hypercalcemia (opposite effect to the one achieved by loop diuretics)
- K+ wasting (excess Na+ is reabsorbed in the collecting tubule) – hypokalemic metabolic alkalosis
- Hypertension
- CHF (adjunct to loop diuretics)
- Nephrolithiasis (urine Ca2+ ↓)
- Nephrogenic diabetes insipidus
- Osteoporosis (serum Ca2+ ↑ promote bone formation)
- Side effects: sulfonamide hypersensitivity, hypokalemic
metabolic alkalosis, hyponatremia, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, Lithium level ↑
Thiazide diuretics and other thiazide derivatives may also act a potent openers of K+-channels, resulting hyperpolarization:
Vasodilation (smooth muscle cell effects)
Insulin release ↓ (pancreatic β-cell effects)
Osteoporosis – definition
Reduction in the strength of bone that leads to an increased risk of fractures; loss of bone tissue is associated with deterioration in skeletal microarchitecture. Main clinical manifestations are vertebral and hip fractures, although fractures can occur at almost any skeletal site.
etiology of osteoporosis
Primary → post-menopausal, senile (age-associated)
Secondary (all are risk -
factors for developing primary osteoporosis) →
Endocrine:
- Hyperparathyroidism
- Hypothyroidism
- Hyperthyroidism
- Hypogonadism
- Pituitary tumors
- Type 1 D.M
GI:
- Malnutrition
- Malabsorption
- Hepatic insufficiency
- Vitamin C, D deficiencies
Drug-induced:
- Anticoagulants
- Chemotherapy
- Corticosteroids
- Anticonvulsants
- Alcohol
Bone mineral density (BMD)
Diagnosis by dual energy X-ray absorptiometry (DEXA) scan, graded based on the T-score.
Classification T-score:
Normal:
-1.0 or greater
Osteopenia:
Between -1.0 to -2.5
Osteoporosis:
-2.5 or less
Severe osteoporosis:
-2.5 or less with a pathologic fracture
Pharmacological management of osteoporosis
I. Inhibit bone resorption:
- Hormonal replacement therapy* : Estrogen (with/without progestin)
- SERM (selective estrogen receptor modulator) : Raloxifene
- Bisphosphonate
- RANK-L inhibitors – Denosumab
- Calcitonin analogues
*Estrogen replacement therapy in post-menopausal women has shown to increase the risk of breast cancer and cardiovascular events.
Currently not recommended as a chronic treatment of osteoporosis!
II. Promote bone formation:
- PTH analogues – Teriparatide
- Ca2+ supplementation
- Vitamin D supplementation
- Thiazide diuretics
