What is the optimal duration of bisphosphonate therapy?
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.
ATYPICAL FEMUR FRACTURES
By March 2011, there were 55 papers describing a total of 283 cases, and about 85 individual cases (listed online in Ott SM. Osteoporosis and Bone Physiology. https://courses.washington.edu/bonephys/opsubtroch.html. Accessed 7/30/2011).
The mean age of the patients was 65, bisphosphonate use was longer than 5 years in 77% of cases, and bilateral fractures were seen in 48%.
The fractures occur with minor trauma, such as tripping, stepping off an elevator, or being jolted by a subway stop, and a disproportionate number of cases involve no trauma. They are often preceded by leg pain, typically in the mid-thigh.
These fractures are characterized by radiographic findings of a transverse fracture, with thickened cortices near the site of the fracture. Often, there is a peak on the cortex that may precede the fracture. These fractures initiate on the lateral side, and it is striking that they occur in the same horizontal plane on the contralateral side.
Radiographs and bone scans show stress fractures on the lateral side of the femur that resemble Looser zones (ie, dark lines seen radiographically). These radiographic features are not typical in osteoporosis but are reminiscent of the stress fractures seen with hypophosphatasia, an inherited disease characterized by severely decreased bone formation.31
Bone biopsy specimens show very low bone formation rates, but this is not a necessary feature. At the fracture site itself there is bone activity. For example, pathologists from St. Louis reviewed all iliac crest bone biopsies from patients seen between 2004 and 2007 who had an unusual cortical fracture while taking a bisphosphonate. An absence of double tetracycline labels was seen in 11 of the 16 patients.32
The first reports were anecdotal cases, then some centers reported systematic surveys of their patients. In a key report, Neviaser et al33 reviewed all low-trauma subtrochanteric fractures in their large hospital and found 20 cases with the atypical radiographic appearance; 19 of the patients in these cases had been taking a bisphosphonate. A similar survey in Australia found 41 cases with atypical radiographic features (out of 79 subtrochanteric low-trauma fractures), and all of the patients had been taking a bisphosphonate.34
By now, more than 230 cases have been reported. The estimated incidence is 1 in 1,000, based on a review of operative cases and radiographs.35
However, just because the drugs are associated with the fractures does not mean they caused the fractures, because the patients who took bisphosphonates were more likely to get a fracture in the first place. This confounding by indication makes it difficult to prove beyond a doubt that bisphosphonates cause atypical fractures.
Further, some studies have found no association between bisphosphonates and subtrochanteric fractures.36,37 These database analyses have relied on the coding of the International Classification of Diseases, Ninth Revision (ICD-9), and not on the examination of radiographs. We reviewed the ability of ICD-9 codes to identify subtrochanteric fractures and found that the predictive ability was only 36%.38 Even for fractures in the correct location, the codes cannot tell which cases have the typical spiral or comminuted fractures seen in osteoporosis and which have the unusual features of the bisphosphonate-associated fractures. Subtrochanteric and shaft fractures are about 10 times less common than hip fractures, and the atypical ones are about 10 times less common than typical ones, so studies based on ICD-9 codes cannot exonerate bisphosphonates.
A report of nearly 15,000 patients from randomized clinical trials did not find a significant incidence of subtrochanteric fractures, but the radiographs were not examined and only 500 of the patients had taken the medication for longer than 5 years.39
A population-based, nested case-control study using a database from Ontario, Canada, found an increased risk of diaphyseal femoral fractures in patients who had taken bisphosphonates longer than 5 years. The study included only women who had started bisphosphonates when they were older than 68, so many of the atypical fractures would have been missed. The investigators did not review the radiographs, so they combined both osteoporotic and atypical diaphyseal fractures in their analysis.40
At the 2010 meeting of the American Society for Bone and Mineral Research, preliminary data were presented from a systematic review of radiographs of patients with fractures of the femur from a health care plan with data about the use of medications. The incidence of atypical fractures increased progressively with the duration of bisphosphonate use, and was significantly higher after 5 years compared with less than 3 years.28
OTHER POSSIBLE ADVERSE EFFECTS
There have been conflicting reports about esophageal cancer with bisphosphonate use.41,42
Another possible adverse effect, osteonecrosis of the jaw, may have occurred in 1.4% of patients with cancer who were treated for 3 years with high intravenous doses of bisphosphonates (about 10 to 12 times the doses recommended for osteoporosis).43 This adverse effect is rare in patients with osteoporosis, occurring in less than 1 in 10,000 exposed patients.44
