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:

• 1^st generation agents:
  • Medronate, clodronate & etidronate
  • Least potent.
• 2^nd generation agents:
  • Alendronate, ibadronate & pamidronate.
  • Half-life of alendronate in bone – 10 years.
  • Long-term use can cause serious adverse effects.
• 3^rd 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.
• 1^st 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 PTH_1-34.
• 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.

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