Treatment of Osteoporosis

TREATMENT OF OSTEOPOROSIS


TREATMENT OF OSTEOPOROSIS

A.) BISPHOSPHONATES:

  • Used for osteoporosis treatment.

MOA:

  • Due to their inhibitory effect on osteoclast-mediated bone resorption.
  • Two mechanisms –
    • By accelerating osteoclastic apoptosis.
    • By suppressing differentiation of osteoclast precursors to mature osteoclasts – By IL-6 inhibition.
  • Reduces cholesterol synthesis via farnesyl pyrophosphate synthase inhibition, by bisphosphonates.

Drugs:

  • 1st generation agents:
    • Medronate, clodronate & etidronate
    • Least potent.
  • 2nd generation agents:
    • Alendronate, ibadronate & pamidronate.
    • Half-life of alendronate in bone – 10 years.
    • Long-term use can cause serious adverse effects.
  • 3rd generation agents:
    • Risedronate & zoledronate.
    • Most potent.
    • Zoledronate infusion of 5mg once yearly.

Uses:

  • Treatment of post-menopausal & steroid-induced osteoporosis.
  • Paget’s disease.
  • Hypercalcemia of malignancy – Mainly pamidronate & zoledronate, by i.v route preferred.
  • Malignancies.
    • Eg: Zoledronate – As an adjunct in treating Philadelphia-chromosome positive CML.

Contraindications:

  • Renal dysfunction
  • Esophageal motility disorders
  • Peptic ulcer.

Adverse effects:

  • Esophageal irritation resulting in ulceration – Distinctive toxicity.
    • Prevented by not taking drug by mouth & not to lie down at least for half an hour.
    • Minimizes chances of drug touching esophagus.
  • Causes hypocalcemia & also, hypercalcemia.
  • 1st generation bisphosphonate – Result in osteomalacia.
  • Zoledronate – Renal toxicity & osteonecrosis of jaw.

Long-term use:

  • Increases risk of atypical ‘chalkstick’ fracture of femur (subtrochanteric or shaft).
    • On concurrent high dose steroid therapy, risk is doubled.
  • Increases risk of esophageal cancer.

B.) SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM)

MOA:

  • Estrogens inhibit bone resorption – 
    • Directly by inhibiting osteoclasts
    • Indirectly by modulating paracrine factors.
  • Increases anti-resorptive [IGF-1 & TGF-β].
  • Suppresses pro-resorptive [IL-1, IL-6, TNF-α, and osteocalcin] factor synthesis by osteoblasts.
  • Increases bone formation.

Use:

  • In Postmenopausal osteoporosis:
    • Estrogen deficiency in old age results in postmenopausal osteoporosis.
    • Use of hormone replacement therapy predisposes patients to adverse effects of estrogens, on breast & endometrium (increased incidence of breast & endometrial carcinoma).

Important drugs:

1. Raloxifene:

  • Exhibits estrogen agonistic action on bone & antagonistic action on breast & endometrium.
  • Hence preferred drug for treatment & prevention of post-menopausal osteoporosis.
  • Adverse effect: Increased risk of thromboembolism (Major).

2. Bazedoxifene:

  • Recently approved SERM for prevention of postmenopausal osteoporosis.
  • Also treats vasomotor symptoms of menopause.

C.) TERIPARATIDE

  • A recombinant PTH1-34.
  • Intermittent s.c. administration.
  • PTH actions:
    • PTH in low & pulsatile dose – Stimulates bone formation.
    • PTH in excess – Causes bone resorption.

MOA:

  • Teriparatide & strontium ranelate stimulates osteoblast.
  • (Most osteoporotic drugs act by inhibiting osteoclast).

Drug effects:

  • Stimulates new collagenous bone.
  • Mineralization of newly formed collagenous bone is essential.
  • Hence, sufficient vitamin D intake & calcium is advised.

Dosage & effects:

  • On administering 20 mcg/d subcutaneously for 2 years – 
    • Teriparatide dramatically improves bone density in most bones, except distal radius.
    • Recommended dose not to be exceeded.
  • Teriparatide course –-> followed by –> bisphosphonates course – Considered for retaining & improving bone density.

Uses:

  • For healing of chalk stick fractures associated with bisphosphonate therapy.

Adverse effects & contraindications:

  • Potential risk of osteosarcoma, on very high doses.
    • Hence, C/I in:
    • Paget’s disease of bone
    • Prior radiotherapy to bone
    • Past history of osteo or chondrosarcoma
  • Unexplained increase in alkaline phosphatase
  • Patient’s on corticosteroids & thiazide diuretics.
  • Oral calcium supplementation advised (due to hypercalcemic risk).

Other adverse effects:

  • Exacerbation of nephrolithiasis.
  • Elevation of serum uric acid levels.

D.) DENOSUMAB:

  • A monoclonal antibody against RANK ligand, useful for osteoporosis treatment.

MOA:

  • Osteoclasts express receptor named ‘receptor for activated nuclear factor κ B (RANK), on its surface.
  • On receptor stimulation, by RANK ligand–> bone resorption occurs.
  • Due to osteoclasts activation.

E.) OSTEOPROTEGERIN:

  • Osteoprotegerin acts as a decoy receptor for RANK ligand.
  • MOA: 
    • Binds it, preventing RANK-L binding to osteoclasts.
  • Uses:
    • Prevents osteoporosis.
    • Recently approved for unresectable giant cell tumor of bone.
  • Drugs effects:
    • Decreases serum calcium – Avoided in hypocalcemic patients.

F.) CINACALCET

  • Cinacalcet – Calcium-sensing receptors present on parathyroid gland.
  • Acts as “calcimimetic drug”.
  • MOA: 
    • By directly Ca2+ activates cinacalcet (calcium-sensing) receptors on parathyroid gland.
  • Uses:
    • Approved for secondary hyperparathyroidism treatment (due to chronic renal disease).
    • Hypercalcemic patients, associated with parathyroid carcinoma.
  • Drug effects:
    • Decreases PTH secretion.
    • Hypocalcemia will have opposite effect, i.e. increases PTH secretion.

G.) STRONTIUM RANELATE

  • Novel drug.
  • Strontium is incorporated into hydroxyapatite, replacing calcium.
  • MOA: Inhibits bone resorption, also stimulates bone formation.

OTHER DRUGS

1. CALCIUM & CALCITRIOL (VITAMIN D):

  • Calcium – 
    • Life-saving in extreme hyperkalemia (> 7 mEg/L).
    • Used in prophylaxis & treatment of osteoporosis.
    • Calcium approved for i.v.treatment of black widow spider envenomation & magnesium toxicity.
    • Reverses some cardiotoxic effects of K+.

2. GALLIUM NITRATE:

  • MOA: 
    • Inhibits bone resorption.
  • Uses:
    • Useful in Paget’s disease management.
    • Hypercalcemia of malignancy.
  • Adverse effect:
    • Nephrotoxicity

3. THIAZIDES

  • MOA: Inhibits renal Ca2+ excretion
  • Uses: Osteoporosis treatment
  • Adverse effect: Recurrent calcium stones due to hypercalciuria.

4. CALCITONIN:

  • MOA: Inhibits bone resorption.
  • Used for osteoporosis treatment.
  • Administered by nasal route (for this indication).
  • Possess analgesic effects on bone pain from fractures.

Exam Important

TREATMENT OF OSTEOPOROSIS

  • Drugs used for treating osteoporosis are bisphosphonates, selective estrogen receptor modulators (SERM), Teriparatide, Denosumab, Osteoprotegerin, Cinacalcet, Strontium ranelate, Calcium, Gallium nitrate & Calcitonin.
  • Bisphosphonates exhibit inhibitory effect on osteoclast-mediated bone resorption.
  • Bisphosphonates cause osteoclast-mediated bone resorption, by accelerating osteoclastic apoptosis & by suppressing differentiation of osteoclast precursors to mature osteoclasts.
  • Least potent bisphosphonates are 1st generation drugs like medronate, clodronate & etidronate.
  • Longest half-life of bisphosphonate in bone is with alendronate for almost 10 years.
  • 3rd generation bisphosphonate drugs like risedronate & zoledronate are the most potent agents.
  • Bisphosphonates are used in treatment of post-menopausal & steroid-induced osteoporosis.
  • Pamidronate & zoledronate, by i.v route is preferred for treating hypercalcemia of malignancy.
  • Distinctive toxicity of bisphosphonates is esophageal irritation & ulceration.
  • Bisphosphonates are not taken by mouth & advised not to lie down, for at least half an hour.
  • 1st generation bisphosphonate results in osteomalacia.
  • On long-term bisphosphonate use, there is increased risk of atypical ‘chalkstick’ fracture of femur (subtrochanteric or shaft).
  • Estrogens inhibit bone resorptiondirectly by inhibiting osteoclast & indirectly by modulating paracrine factors.
  • Selective estrogen receptor modulators (SERM) increases anti-resorptive, suppresses pro-resorptive factor synthesis by osteoblasts & increase bone formation.
  • SERM is useful for treating postmenopausal osteoporosis.
  • Estrogen deficiency in old age results in postmenopausal osteoporosis.
  • Raloxifene, a SERM exhibits estrogen agonistic action on bone & antagonistic action on breast & endometrium.
  • Raloxifene, a SERM is a preferred drug for treatment & prevention of post-menopausal osteoporosis.
  • Bazedoxifene is a recently approved SERM for prevention of postmenopausal osteoporosis.
  • Bazedoxifene also treats vasomotor symptoms of menopause.
  • Teriparatide is a recombinant PTH1-34.
  • Teriparatide & strontium ranelate stimulates osteoblast.
  • Most osteoporotic drugs act by inhibiting osteoclast.
  • PTH in low & pulsatile dose stimulates bone formation.
  • PTH in excess causes bone resorption.
  • Teriparatide stimulates new collagenous bone.
  • Sufficient vitamin D intake & calcium is advised concurrently during teriparatide therapy.
  • On administering Teriparatide 20 mcg/d subcutaneously for 2 years, dramatically improves bone density in most bones, except distal radius.
  • Teriparatide course is followed by bisphosphonates course mainly considered for retaining & improving bone density.
  • Teriparatide is used for healing of chalk stick fractures associated with bisphosphonate therapy.
  • Denosumab is a monoclonal antibody against RANK ligand, useful for osteoporosis treatment.
  • Osteoclasts have a surface receptor named ‘receptor for activated nuclear factor κ B (RANK), which on stimulation by RANK ligand causes bone resorption.
  • Osteoprotegerin acts as a decoy receptor for RANK ligand.
  • Osteoprotegerin binds RANK receptors, preventing RANK-L binding to osteoclasts.
  • Cinacalcet is a calcium-sensing receptor present on parathyroid gland.
  • Cinacalcet acts as “calcimimetic drug”.
  • Cinacalcet is approved for secondary hyperparathyroidism treatment.
  • PTH secretion is decreased by Cinacalcet.
  • Strontium ranelate inhibits bone resorption as well as stimulates bone formation.
  • Calcium is a life-saving in extreme hyperkalemia (> 7 mEg/L).
  • Calcium is approved for i.v.treatment of black widow spider envenomation & magnesium toxicity.
  • Calcitonin inhibits bone resorption.
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