Current Drug Therapy

What is the optimal duration of bisphosphonate therapy?

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ABSTRACTIt is reasonable to stop bisphosphonates after 5 years of use and then to follow patients with markers of bone turnover. As long as the levels of these markers remain reduced, adding an antiresorptive drug does not make physiologic sense.

KEY POINTS

  • Bisphosphonates reduce the risk of osteoporotic fractures, including devastating hip and spine fractures.
  • As with any drugs, bisphosphonates should not be used indiscriminately. They are indicated for patients at high risk of fracture, especially those with vertebral fractures or a hip bone density T score lower than −2.5.
  • There is little evidence to guide physicians about the duration of bisphosphonate therapy beyond 5 years. One study with marginal power did not show any difference in fracture rates between those who continued taking alendronate and those who discontinued after 5 years (JAMA 2006; 296:2927–2938).
  • Evidence is accumulating that the risk of atypical fracture of the femur increases after 5 years of bisphosphonate use.
  • Anabolic drugs are needed; the only one currently available is teriparatide (Forteo), which can be used when fractures occur despite (or perhaps because of) bisphosphonate use.


 

References

Almost all the data about the safety and efficacy of bisphosphonate drugs for treating osteoporosis are from patients who took them for less than 5 years.

Reports of adverse effects with prolonged use have caused concern about the long-term safety of this class of drugs. This is particularly important because these drugs are retained in the skeleton longer than 10 years, because there are physiologic reasons why excessive bisphosphonate-induced inhibition of bone turnover could be damaging, and because many healthy postmenopausal women have been prescribed bisphosphonates in the hope of preventing fractures that are not expected to occur for 20 to 30 years.

Because information from trials is scant, opinions differ over whether bisphosphonates should be continued indefinitely. In this article, I summarize the physiologic mechanisms of these drugs, review the scant existing data about their effects beyond 5 years, and describe my approach to bisphosphonate therapy (while waiting for better evidence).

MORE THAN 4 MILLION WOMEN TAKE BISPHOSPHONATES

The first medical use of a bisphosphonate was in 1967, when a girl with myositis ossificans was given etidronate (Didronel) because it inhibited mineralization. Two years later, it was given to patients with Paget disease of bone because it was found to inhibit bone resorption.1 Etidronate could not be given for longer than 6 months, however, because patients developed osteomalacia.

Adding a nitrogen to the molecule dramatically increased its potency and led to the second generation of bisphosphonates. Alendronate (Fosamax), the first amino-bisphosphonate, became available in 1995, It was followed by risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast). These drugs are potent inhibitors of bone resorption; however, in clinical doses they do not inhibit mineralization and therefore do not cause osteomalacia.

Randomized clinical trials involving more than 30,000 patients have provided grade A evidence that these drugs reduce the incidence of fragility fractures in patients with osteoporosis.2 Furthermore, observational studies have confirmed that they prevent fractures and have a good safety profile in clinical practice.

Therefore, the use of these drugs has become common. In 2008, an estimated 4 million women in the United States were taking them.3

BISPHOSPHONATES STRENGTHEN BONE BY INHIBITING RESORPTION

On a molecular level, bisphosphonates inhibit farnesyl pyrophosphate synthase, an enzyme necessary for formation of the cytoskeleton in osteoclasts. Thus, they strongly inhibit bone resorption. They do not appear to directly inhibit osteoblasts, the cells that form new bone, but they substantially decrease bone formation indirectly.4

To understand how inhibition of bone resorption affects bone physiology, it is necessary to appreciate the nature of bone remodeling. Bone is not like the skin, which is continually forming a new layer and sloughing off the old. Instead, bone is renewed in small units. It takes about 5 years to remodel cancellous bone and 13 years to remodel cortical bone5; at any one time, about 8% of the surface is being remodeled.

The first step occurs at a spot on the surface, where the osteoclasts resorb some bone to form a pit that looks like a pothole. Then a team of osteoblasts is formed and fills the pit with new bone over the next 3 to 6 months. When first formed, the new bone is mainly collagen and, like the tip of the nose, is not very stiff, but with mineral deposition the bone becomes stronger, like the bridge of the nose. The new bone gradually accumulates mineral and becomes harder and denser over the next 3 years.

When a bisphosphonate is given, the osteoclasts abruptly stop resorbing the bone, but osteoblasts continue to fill the pits that were there when the bisphosphonate was started. For the next several months, while the previous pits are being filled, the bone volume increases slightly. Thereafter, rates of both bone resorption and bone formation are very low.

A misconception: Bisphosphonates build bone

While semantically it is true that the bone formation rate in patients taking bisphosphonates is within the normal premenopausal range, this often-repeated statement is essentially misleading.

Copyright Susan Ott, used with permission

Figure 1. Mineralization surfaces in studies of normal people and with osteoporosis therapies. Mineralization (tetracycline-labelled) surfaces are directly related to the bone formation rate. Each point is the mean for a study, and error bars are one standard deviation. The clinical trials show the values before and after treatment, or in placebo vs medication groups.

The most direct measurement of bone formation is the percentage of bone surface that takes a tetracycline label, termed the mineralizing surface. Figure 1 shows data on the mineralizing surface in normal persons,6 women with osteoporosis, and women taking various other medications for osteoporosis. Bisphosphonate therapy reduces bone formation to values that are lower than in the great majority of normal young women.7 A study of 50 women treated with bisphosphonates for 6.5 years found that 33% had a mineralizing surface of zero.8 This means that patients taking bisphosphonates are forming very little new bone, and one-third of them are not forming any new bone.

With continued bisphosphonate use, the bone gradually becomes more dense. There is no further new bone, but the existing bone matrix is packed more tightly with mineral crystals.9 The old bone is not resorbed. The bone density, measured radiographically, increases most rapidly during the first 6 months (while resorption pits are filling in) and more gradually over the next 3 years (while bone is becoming more mineralized).

Another common misunderstanding is that the bone density increases because the drugs are “building bone.” After 3 years, the bone density in the femur reaches a plateau.10 I have seen patients who were very worried because their bone density was no longer increasing, and their physicians did not realize that this is the expected pattern. The spinal bone density continues to increase modestly, but some of this may be from disk space narrowing, harder bone edges, and soft-tissue calcifications. Spinal bone density frequently increases even in those on placebo.

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