Bisphosphonate Drugs
Bisphosphonates bind strongly to the calcium compounds in the bone and interfere with osteoclasts, which are the bone cells that break down the mineral structure of the bone. The drugs block bone resorption. They have been widely used for years and although there can be side effects, the medical profession considers them generally safe and effective.
Most are taken orally, as a pill, either once a day or once a week. Bisphosphonates can be given intraveneously; formulations are available for patients who cannot tolerate oral bisphosphonates. Some patients cannot sit upright for 30 to 60 minutes which is a requirement for some drugs. The bisphosphonate zoldronate can be administered through a patch.
Bisphosphonates are employed for:
- treatment and prevention of postmenopausal osteoporosis
- treatment to increase bone mass in men with osteoporosis
- treatment and prevention of glucocorticoid induced osteoporosis
- treatment of Paget’s disease
- prevention of Skeletal Relevant Events (bone fractures)
- treatment of the hypercalcemia of malignancy
- bone loss caused by cancer treatment
- bone loss and bone pain caused by bone cancer and metastases. Bisphosphonates slow the loss of bone density caused by metastatic cancer and have been shown to increase life expectancy in patients.
- osteoporosis imperfecta in children, where they have been very successful in cutting down the number of operations these patients need
Bisphosphonates approved for use in the United States include:
- Fosamax (alendronate), available in generic formulation
- Fosamax with D (alendronate with Vitamin D)
- Actonel (risedronate)
- Actonel with Calcium (risedronate with calcium)
- Boniva (ibandronate)
- Reclast (zoledronic acid)
- Zometa (zoledronic acid)
- Didronel (etidronate) available in generic formulation
- Aredia (pamidronate) available in generic formulation
- Skelid (tiludronate)
Doctors use bisphosphonates for any excessive bone resorption, not just osteoporosis. Hypercalcemia and Paget disease are among the other conditions treated.
Bisphosphonates bind strongly to the hydoxyapatite in the bone and interferes with osteoclasts, which are the bone cells that break down bone. Hydoxyapatite is a calcium phosphorus compound that makes up about half of bone mass. Zoledronate can be administered with a patch.
Some bisphosphonate medicines are nitrogen compounds – their molecules include nitrogen atoms. These include the most widely used bisphosphonates: risedronate, pamidronate, ibandronate, alendronate, and zoledronate. These nitrogen compound bisphosphonates more effectively slow boney material resorption to the blood than the simple bisphosphonates: etidronate, clodronate, and tiludronate.
At a biochemical level, there are differences in how the two types (nitrogen-containing vs simple) work. This is pretty technical, but the simple drugs are metabolized by the osteoclasts and the resulting metabolites are essentially poisonous to the osteoclasts. The nitrogen-compound drugs disrupt protein prenylation, which moves to help detach the osteoclasts from the bone mass.
Drug specifics
Fosamax (alendronate), manufactured by Merck
Market Share and Sales:
Held 40% market share with estimated sales of over $3 billion in 2007. In
2008 the patent expired and generics became available. Merck's market share
for branded Fosamax is now under 10%.
Dosage and Forms:
10mg and 70mg tablet
- 10mg tablet daily or
- 70mg tablet weekly
Generic formulations manufactured by:
- Teva Pharmaceuticals USA (US)
- Barr Pharmaceuticals, Inc. (US, acquisition of Teva)
- Watson Pharmaceuticals, Inc. (US)
- Mylan, Inc.(US)
- Genpharm, Inc. (Canada, division of Mylan)
- Apotex Corp/Major Pharmaceuticals (Canada)
- Cobalt Pharmaceuticals (Canada)
- Sun Pharmaceuticals (India)
- Dr. Reddy’s Laboratories, Ltd. (India)
- Aurobindo Pharma (India)
Approved Indications for use:
- treatment and prevention of postmenopausal osteoporosis
- treatment to increase bone mass in men with osteoporosis
- treatment and prevention of glucocorticoid induced osteoporosis
- treatment of Paget’s disease
Non-approved but known (off label) uses
- Vitamin D overdose
- Osteoporosis caused by spinal injury.
Fosamax with D (alendronate with Vitamin D) manufactured by Merck
Approved for use in 2005
Dosage and Forms:
- once weekly – 70mg/5,600U tablet
- once weekly - 70mg/2,800U tablet
Approved Indications
- Treatment of Osteoporosis in Postmenopausal Women
- Treatment to Increase Bone Mass in Men with Osteoporosis
Non-approved but known (off label) uses
- Treating or preventing glucocorticoid induced osteoporosis
- Prevention of osteoporosis in postmenopausal women
Actonel (risedronate) manufactured by Procter and Gamble / Sanofi-Aventis
Market Share and Sales:
Held estimated 29% market share with estimated sales of over $1.1 billion
in 2008. The patent will expire in 2011 and generic forms should be available.
Dosage and Forms:
5mg, 35mg, 75mg and 150mg tablet
- 5mg tablet daily or
- 35mg tablet weekly or
- 75mg tablet taken on 2 consecutive days one time each month or
- 150mg tablet monthly
Approved Indications for use:
- treatment and prevention of postmenopausal osteoporosis
- treatment to increase bone mass in men with osteoporosis
- treatment and prevention of glucocorticoid induced osteoporosis
- treatment of Paget’s disease
Non-approved but known (off label) uses
- Hypercalcemia
- Bone Cancer or Bone Metastases
Actonel with Calcium (risedronate with calcium) manufactured by and Procter and Gamble / Sanofi-Aventis
Approved in 2005.
Dosage and Forms:
Blister Package containing one (1) 35mg Actonel and six (6) 1250mg calcium
carbonate tablets
o Actonel taken on day 1 and calcium taken on days 2 - 7
Approved Indications for use:
- Treatment of Osteoporosis in Postmenopausal Women
- Treatment to Increase Bone Mass in Men with Osteoporosis
Non-approved but known (off label) uses
- Treatment of glucocorticoid induced osteoporosis
- Treatment of Paget’s disease
Boniva (ibandronate) manufactured by Roche
Market Share and Sales:
Annual sales exceed $1 billion.
Dosage and Forms:
- 2.5mg tablet and 150mg tablet
- 2.5mg daily or
- 150 mg monthly
Approved Indications for use:
- treatment and prevention of osteoporosis in postmenopausal women
Non-approved but known (off label) uses
- Hypercalcemia of malignancy
- Treatment of Paget's disease
- bone cancer or bone metastases
- treatment and prevention of Osteoporosis in men or premenopausal women.
Reclast (zoledronic acid) manufactured by Novartis Pharmaceuticals
Dosage and Forms:
- 5 mg IV injection performed by infusion clinic once yearly.
Approved Indications for use:
- treatment of postmenopausal osteoporosis
- treatment to increase bone mass in men with osteoporosis
- treatment of glucocorticoid induced osteoporosis
- treatment of Paget’s disease
Non-approved but known (off label) uses
- Prevention of osteoporosis
- treatment of osteoporosis in premenopausal women
Zometa (zoledronic acid) manufactured by Novartis
Dosage and Forms:
- 4mg IV injection every 3 to 4 weeks depending upon patient condition (minimum 7 days between injections)
Approved indications for use:
- treatment to reduce and delay bone complications due to multiple myeloma and bone metastases from solid tumors
Non-approved but known (off label) uses
- Hypercalcemia of malignancy
Didronel (etidronate) Procter and Gamble Pharmaceuticals
Dosage and Forms:
- Heteropic ossification - 10-20mg/kg IV daily for 10 weeks
- Paget’s disease - 5mg/kg IV daily for 6 months
generic formulations manufactured by:
- Mylan, Inc.(US)
- Genpharm, Inc. (Canada, division of Mylan)
Approved Indications for use:
- Treatment of Paget's disease
- Prevention or treatment of heterotopic ossification after total hip replacement surgery or spinal cord injury.
Non-approved but known (off label) uses
- Treatment of osteoporosis
Aredia (pamidronate) available in generic formulation
Dosage and Forms:
Injectable (IV) available in 30mg and 90mg vials
- Paget’s disease 30mg qd for 3 days
- Bone cancer 90mg q 3-4 weeks
- Hypercalcemia 60-90mg depending upon therapeutic response.
Generic formulations manufactured by: Bedford labs
Approved Indications for use:
- Hypercalcemia of malignancy
- Treatment to reduce and delay bone complications due to multiple myeloma and bone metastases from solid tumors
- Treatment of Paget’s disease
Non-approved but known (off label) uses
- Hypercalcemia due to hyperparathyroidism
- Osteogenesis imperfecta (a genetic bone defect)
- Osteoporosis.
Skelid (tiludronate) manufactured by Sanofi-Aventis
Patent expired in 2009 but little chance for generic manufacturing due to limited use.
Dosage and forms
240mg tablet equivalent to 200mg tiludronic acid
- Paget’s disease - 400mg tiludronic acid (2 tablets) daily for 3 months
Approved Indications for use:
- Treatment of Paget’s disease
Non-approved but known (off label) uses
- None
Legal Troubles
Bisphosphonates were at the center of a bunch legal trouble because of a omplication known as "Dead Jaw Syndrome" or Osteonecrosis of the Jaw. The lawsuits were primarily targeted against the makers of Fosamax but all bisphosphonates may potentially cause this disease.
Going Forward
Some experts are questioning the use of bisphosphonates for patients with osteopenia. And osteoporosis patients on bisphosphonates might consider discussing a "drug holiday" with their doctors, during which they would stop taking the drug for a while. In Sept 2011 the FDA in a staff report said that most women could stop taking bisphonates after 5 years, as the marginal benefit from continued use was minimal.
Recently, Japanese astronauts on the International Space Station took bisphosphonates once a week and reportedly suffered no bone loss despite being in weightless conditions for more than 130 days. People who spend a lot of time in low gravity environments often experience bone loss.
Clearly despite side effects and adverse event potential, this class of drug is beneficial to many and has been a major tool in the treatment of bone disorders. Bisphosphonates have been successful, both medically and business-wise, with annual sales at over $3.5 billion.
Related
Risks and benefits of long-term bisphosphonate therapy.
Last updated: Jan 20, 2012
