bisphosphonate

Introduction

Group of compounds that bind to hydroxyapatite & inhibits osteoclast activity.

Indications

• osteoporosis
  • post-menopausal women
  • chronic glucocorticoid use, > 5 mg/day (prednisone) for more than 3 months
  • hypogonadism
    • androgen-deprivation therapy for prostate cancer
  • bone mineral density < -2.5 (i.e. -2.6 or -2.8)*
  • prior fracture (vertebral fracture, hip fracture, fragility fracture)
  • high-risk by FRAX
  • 10 year risk of hip fracture >= 3%
  • 10 year probability of major osteoporotic fracture >= 20%
• osteopenia with high risk factors (see FRAX risk assessment tool)
  • bisphosphonate cost-effective when 10 year risk of major osteoporotic fracture is >= 20% or risk of hip fracture is >= 3%
• excessive or disordered osteoclastic activity associated with
  • Paget's disease of bone
  • hypercalcemia
  • bone metastases
    • osteolytic bone metastases of breast cancer
    • osteolytic bone lesions of multiple myeloma
• dystrophic calcification
• bisphosphates lower breast cancer recurrence & mortality in postmenopausal women
  • bisphosphates do not reduce risk of breast cancer

Contraindications

(cautions)

• limit therapy to 3-5 years (saturation of benefit)
• use with caution in premenopausal women
• use controversial in patients with chronic renal failure stage 3 or greater (GFR < 30 mL/min/1.73 m2)
• use to treat osteoporosis not associated with lower mortality
• IV bisphosphonates contraindicated in patients with hypocalcemia
• oral bisphosphates contraindicated in patients with esophageal varices
• vitamin D deficiency (osteoporosis)

Benefit/risk

• postmenopausal women with prior fracture or very low bone density
  • number needed to treat (NNT)
    • 20 women for 3 years to prevent 1 vertebral fracture
    • 100 women for 3 years to prevent 1 hip fracture
    • 100 postmenopausal women with osteoporosis for 12.4 months to prevent one nonvertebral fracture
  • number needed to harm
    • a small number of women are harmed
      • harms not well studied
• postmenopausal women without prior fracture or very low bone density
  • no benefit for preventing fractures within 3 years
  • a small number of women are harmed
• treatment of osteoporosis with a bisphosphonate has an expected time-to-benefit of 1-2 years

Dosage

• separate from calcium supplement
• duration of therapy: 3-5 years for most patients
  • discontinue bisphosphonate therapy after 2-5 years
• 5 years for alendronate, 3 years for zoledronate*
  • continue alendronate 10 years in women with history of osteoporotic fracture (high-risk) with stable bone density
• 5 years for bisphosphonates
  • no benefit for >5-7 years of therapy
• reassess fracture risk after 5 years for alendronate, 3 years for zoledronate
  • for women at high risk (low T score, previous osteoporotic fracture), oral therapy may be continued for up to 10 years or IV therapy for up to 6 years
  • continued treatment can prevent bone loss & reduce risk for vertebral fractures
  • no data to support continued bisphosphonate therapy > 5 years for risk reduction of hip fracture
  • fracture risk should be reassessed every 2-3 years during this extended treatment

* correct vitamin D deficiency prior to administration for osteoporosis

* bone loss after discontinuation of therapy may be greater for risedronate than alendronate or zoledronate

* no data to guide duration of ibandronate therapy

Pharmacokinetics

• poorly absorbed orally, 1-5% of oral dose
  • food interferes with absorption
• plasma 1/2life of 1 hour
• eliminated in urine (80%)
• 20% of absorbed dose taken up by bone
• bisphosphonate may persist in bone for lifetime

Monitor

• routine monitoring of bone mineral density after initiating bisphosphonate therapy is costly & unwarranted

Adverse effects

• nausea/vomiting
• erosive esophagitis
• ocular inflammation
  • conjunctivitis, blurred vision, eye pain (uncommon)
  • uveitis (RR=1.45) & scleritis (RR=1.51)
• osteonecrosis of the jaw (especially IV administration)
• inhibition of normal bone repair of microdamage that occurs during activities of daily living
  • despite this, IV zoledronate recommended within 14-90 days after hip fracture surgery
• long-term therapy (> 5 years) may increase risk of minimal trauma fractures of the femur
  • atypical subtrochanteric stress fracture
  • > 70% of patients with weight-bearing pain prior to atypical fracture
  • 277 atypical femur fractures observed in 196,129 women over 10 years
  • benefit exceeds risk 149:2 (whites) vs 91:8 (Asians)
• severe joint pain, musculoskeletal pain (intravenous & oral) uncommon
• duration of therapy
  • after 3-5 years of bisphosphonate therapy, risk may exceed benefit*
  • benefit/risk ratio remains favorable for > 10 years in postmenopausal women with osteoporosis
• increases bone mineral density, but also increases risk of hip fracture in primary hyperparathyroidism relative to observation (RR=1.5)

* American Board of Internal Medical appears to endorse long term bisphosphonate use, citing

• drug adverse effects of bisphosphonates

Mechanism of action

• binds to hydroxyapatite & inhibits osteoclast activity
• reduces osteoclast number
• stimulates formation of osteoblast precursors
• 97% of patients show clinically beneficial increases in bone mineral density at the hip density after 3 years of treatment

Notes

• possible association with bisphosphonates & reduced risk of breast cancer
• bisphosphonate use is associated with a lower rate of revision after hip arthroplasty & knee arthroplasty & longer implant survival

More general terms

• endocrine agent
• musculoskeletal system agent

More specific terms

• alendronate (Fosamax, Fosamax Plus D, Binosto)
• clodronate; clodronic acid (Clodronsaeure, Clasteon, Bonefos, Loron)
• etidronate (Didronel)
• ibandronate; ibandronic acid (Boniva, Bondronat)
• pamidronate (Aredia)
• risedronate (Actonel)
• tiludronate (Skelid)
• zoledronate (Zometa, Reclast)