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Bisphosphonates can be a useful part of osteoporosis therapy. But used for too long or used as a stand-alone therapy they can make the condition worse.

Bisphosphonates are a class of medications for osteoporosis. These drugs harden bones and prevent further deterioration and fractures. They work against osteoporosis by slowing down the bone’s process of resorption, which clears out old bone so it can be replaced by new bone, leaving bone super-hard.

Is it bisphosphonate or diphosphonate? Not all of the English-speaking world uses the same term for these osteoporosis medications. The reason for the variation of terminology is the chemistry of the drug. Each molecule of a bisphosphonate consists of two phosphate groups to a central carbon atom. This carbon atom is attached to two other groups of atoms that determine how the bisphosphonate as a whole reacts with bone. Bisphosphonates are also sometimes termed diphosphonates, due to the coupled chemistry of the compound.

Among the drugs in this class are:

  • Alendronate (Fosamax)
  • Clodronate (Bonefos, Loron)
  • Etidronate (Didronel)
  • Ibandronate (Boniva - US, Bonviva - Asia)Neridronate (Nerixia)
  • Olpadronate
  • Pamidronate (APD, Aredia)
  • Risedronate (Actonel)
  • Tiludronate (Skelid)
  • Zoledronate (Zometa, Aclasta)

Bisphosphonates were originally used to soften water used in orange groves. They had been commonly available in agriculture for over 70 years before researchers recognized that these chemicals could stop the buildup of many kinds of crystals in irrigation pipes, but they were not effective in stopping the production of a kind of crystal called hydroxyapatite.

Why should this make a difference in osteoporosis?

Sometimes the problem in osteoporosis is that specialized cells called osteoclasts are too numerous or too active. These cells break down bone, but they can only destroy bone when they are covered with a crystalline “ruffle” that maintains contact with their target cells. Bisphosphonates break down the ruffle so osteoclasts cannot break down bone.

The maintenance of healthy bone requires two different kinds of cells. Osteoclasts break down old bone to repair fractures and strengthen the outside of the bone to accommodate changes in the physical stress placed on it. Osteoblasts create strings of protein called collagen that “glue” mineral crystals together to make the bone both strong and flexible.

The problem with bisphosphonates is that by shutting down bone’s break-down process, they deprive the bone of the raw materials to rebuild it. It’s as if the bone runs an overdraft at its calcium bank to keep old bones hard without leaving enough calcium and other minerals for new bone. After a few years, bisphosphonates can start reducing bone mineral density instead of increasing it. And because the old crystals are continuously reinforced without building new collagen scaffolding to hold the bone together, super-hard bones may shatter when they are fractured, making healing slower or impossible.

That’s the reason that bisphosphonate therapy by itself is never enough to prevent osteoporosis or to bring its progression under control. The doctor needs to take a holistic look at hormones such as estrogen (in women) and testosterone (in men), and the patient needs to follow appropriate diet, nutritional supplementation, and exercise, and take precautions against falls.

Bisphosphonates have side effects, some of which are aggravated by medications taken to counteract side effects

There is one scary but rare complication of bisphosphonate therapy: osteonecrosis of the jaw bone. Oversuppression of the osteoclasts can interfere with remodeling of the jaw so that tissue inside the bone dies. This condition can lead to infection with unrelenting pain and disfigurement, and it is very resistant to treatment. It is most common in younger people (40 and under) who are put on bisphosphonates, but it only occurs about once in 100 cases when used to treat bone fractures due to cancer and once in 100,000 to 250,000 cases otherwise.

There is also some speculation that bisphosphonates can trigger atrial fibrillation, although the link is not certain.

There are other less severe complications of bisphosphonate use that are much more common. There can be increased bone pain, increased joint pain, stomach pain, nausea, gas, and indigestion. When the doctor prescribes proton pump inhibitors to deal with stomach problems caused by bisphosphonates, the combination can reduce calcium absorption so much that more fractures occur.

These less severe side effects of bisphosphonate treatment often cause people to stop taking this potentially helpful drug. Work with your doctor to stay comfortable so you can take advantage of the treatment as long as possible.

The bottom line on bisphosphonates

The potential for problems with bisphosphonates does not mean that they never should be prescribed. But the potential for side effects requires that these useful drugs should be:

  • Reserved for serious cases,
  • Always accompanied by daily mineral supplementation, and
  • Tapered off as quickly as possible as DEXA scores improve,

There is one additional precaution always required with bisphosphonates.

An essential laboratory test for anyone who takes bisphosphonates

The bone-specific alkaline phosphatase test is a must for anyone to takes any bisphosphonate medication. Bone-specific alkaline phosphatase (bsALP) detects the early signs of osteoblastic activity. This is a measure of the activity of the bone-building cells known as osteoblasts. When someone who has osteoporosis is being given too high a dose of bisphosphonate therapy, the bone-recycling osteoclasts (a different kind of cell) are shut down. But the osteoclast (bone recyclers) stimulate the osteoblasts (bone builders). It’s possible to shut down bone recycling so thoroughly that bone building is shut down, too.

  • Abrahamsen B., Eiken P., Eastell R. (2009) More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360: 1789–1792.
  • Aguirre L.E., Lewiecki E.M. (2009) Management of osteoporosis in elderly women. Ann Long-Term Care: Clin Care Aging 17(10): 35–39. Harrington J.T., Barash H.L., Day S., Lease J. (2005) Redesigning the care of fragility fracture patients to improve osteoporosis management: a health care improvement project. Arthritis Rheum 53: 198–204.
  • Wilkes M.M., Navickis R.J., Chan W.W., Lewiecki E.M. (2010) Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials. Osteoporos Int 21: 679–688.
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