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 intravenously; formulations are available for patients who cannot tolerate oral bisphosphonates. Some taking pillspatients cannot sit upright for 30 to 60 minutes which is a requirement for some drugs. The bisphosphonate zoledronate 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 Related Events (bone problems caused by cancer metastasis)
  • treatment of the hypercalcemia of malignancy
  • bone loss caused by cancer treatment
  • 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's disease are among the other conditions treated.

Bisphosphonates bind strongly to the hydroxyapatite in the bone and interferes with osteoclasts, which are the bone cells that break down bone. Hydroxyapatite is a calcium phosphorus compound that makes up about half of bone mass. Compared to other drugs, bisphosphonates stay in the body a very long time. Most drugs are excreted or metabolized by the body in a day or two. Bisphosphonates stay in the body for years.

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. (There is evidence that nitrogen-containing bisphosphonates can reduce the risk of breast cancer.)

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

Alendronate (Fosamax), developed by Merck

Market Share and Sales:
In 2008 the patent expired and generic formulations of this drug became available. Merck's market share for branded Fosamax is now under 10%. Generic alendronate from other manufacturers now domainates the market.

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

Side Effects

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


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


The patent expired in 2011 and generic forms are now 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)


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:

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
  • Paget's disease
  • Bone cancer or bone metastases
  • Treatment and prevention of Osteoporosis in men or premenopausal women.

The patent for ibandronte expired and the FDA approved generic versions in March of 2012.


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

Binosto (alendronate)

Binosto is alendronate, but delivered in a different form. It is an effervescent tablet that the patient takes once a week. The manufacturer hopes that if it goes down easier than the pill form and will be attractive for that reason.

Legal Troubles

Bisphosphonates were at the center of legal trouble because of a complication 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.

Safety Concerns

A recent study found evidence that bisphosphontes increase the risk of thigh fracture. The increased risk, although small, gets higher the longer the patient takes the medication. The problem appears to be that the some bone resorption is important in healthy bone physiology, and that the bisphosphonates are too effective in stopping turnover.

The FDA issued an advisory that doctors should reassess the use of these drugs, given concerns about side effects and scant evidence that the drugs help people without osteoporosis. The FDA requires bisphosphonates be labeled "the optimal duration of use has not been determined."

Here is a situation where the doctor must formulate a strategy. Younger patients and patients considered at lower risk for fractures, may be better candidates for discontinuing bisphosphonate therapy after a few years.

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 bisphosphonates after 5 years, as the marginal benefit from continued use was minimal. A study published in 2014 concluded patients who had taken alendronate for three years could safely take a one year holiday with no increase in fracture risk.

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.

Related: Risks and benefits of long-term bisphosphonate therapy.

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Protect Your Bones

1) Exercise (ideally including some resistance exercise to build strength.)

2) Eat a healthy diet. Pay special attention to your daily requirement for Vitamin D and calcium.

3) Don't smoke and avoid excessive alcohol.

4) Follow your doctor's advice and get bone density tests as he or she suggests.

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