Primary Care Corner with Geoffrey Modest MD: Long Term Alendronate Effectiveness and Safety

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By Dr. Geoffrey Modest

There have been concerns that long-term alendronate use could lead to more complications, such as subtrochanteric femur fractures, but a recent Danish registry study was reassuring (See doi: 10.1136/bmj.i3365).

Details:

  • 61990 men and women 50-94 yo on alendronate, in the Danish prescription registry from 1996-2007, which holds almost 20 years of drug exposure data, were linked to all fracture outcomes treated in-hospital.
  • Mean age 72, 83% women, baseline major osteoporotic fracture 31%, diabetes 5%, CKD 1%, chronic pulmonary disease 19%, prednisolone in past year 25%
  • 2 nested case-control studies: one looked at those with hip fractures and compared them to 3 controls matched for age, sex, year of starting treatment, and follow-up time; the other similarly-controlled looked at subtrochanteric/femur shaft (ST/FS) fracture but matched to 5 controls.
  • All alendronate dosing was at 70 mg/week. Mean follow-up 6.9 years (range 0-17.9)
  • Results: [though of those who took their meds regularly, only 30% (18,242) completed 5 years of treatment, 4% (2465) completed 10 years, and only about 1000 completed >=14 years]
    • Incident ST/FSfracture in 1428 people, at rate of 3.4/1000 person-years (CI 3.2-3.6)
    • Incident hip fracture in 6784 people, at rate of 16.2/1000 person-years (CI 15.8-16.6)
    • Higher medication adherence and longer term use of alendronate led to 27% decreased risk of hip fracture [HR 0.73 (0.68-0.78), p<0.001]
    • Longer term alendronate usage was associated with decreased risk of hip fracture:
      • 5-10 dose years: HR 0.75 (0.67-0.83), p<0.001
      • >10 dose years: HR 0.74 (0.56-0.97), p=0.03
    • There was no association of ST/FS fracture with cumulative use of alendronate in those taking alendronate >10 years (in fact, there was a 57% reduced risk of subtrochanteric femur fractures and no change in shaft fractures), or in those currently taking it vs past users, though the likelihood of ST/FS was higher in those with comorbidities including diabetes, chronic lung disease, and those on proton pump inhibitors (PPIs).
    • The NNT (number-needed-to-treat for an additional 5 year to prevent one additional fracture) was 38, and the NNH (number-needed-to-harm by causing a ST/FS fracture in one person with an additional 5 years of therapy) was 1449.

Commentary:

  • There has been concern that using prolonged bisphosphonates could lead to more problems with atypical femur fractures, and, perhaps related to that, the usage of these meds has decreased by 50% in the US and similarly in the European Union
  • The above Danish study is observational, and therefore subject to biases. So, hard to make a firm recommendation. Potential biases and limitations include:
    • The registry was almost exclusively of North Europeans. There is some concern that some groups (e.g. South Asians) may be at higher risk of atypical femur fractures
    • They did not look at osteonecrosis of the jaw, another uncommon event related to bisphosphonates
    • The consequences/morbidity of an atypical hip fracture can be high, though typically less than that of a regular hip fracture
    • The above data were more impressive in those patients who adhered more to treatment with alendronate, and this group might be different from the general population (perhaps educational differences, or this group was convinced they were at higher risk of fracture and took the meds more often, etc.)
    • They did not have data on calcium/vitamin D intake.
  • In the Danish study, assuming a worst-case scenario (i.e., 100% of the ST/FS fractures are atypical/related to alendronate, there was 0 background rate of these fractures, and comparing the upper 95% confidence limit in the harm:benefit models rather than the observed 50% rate), there was still a clear benefit of alendronate for up to 13 years (and part of the issue beyond that is that there were so few patients on the med for >11 years that the confidence intervals were quite wide)
  • There are some data from a randomized trial (see Bone, HG. N Engl J Med. 2004; 350: 1189) where a subset of postmenopausal women were randomized to stopping alendronate after 5 years or continuing another 5 years, finding some decrease in BMD and increase in markers of bone turnover in the former group but no significant difference in fractures (except for slightly higher risk of fractures detected by x-ray and some nonsignificant decrease in height loss). But it is important to note that women at higher risk of fracture were excluded(either T-scores below -3.5, or T-score after 5 years which was worse than their baseline). No one in either group developed jaw osteonecrosis, and bone biopsies showed no qualitative abnormalities.
  • So, the above data are impressive, suggesting that continued alendronate, even up to 14+ years, is associated with continued decrease in hip fracture risk and no real change in ST/FS. My approach, which is reinforced by this Danish study, is to put all patients with an osteoporotic fracture or a BMD less than -3.5 on long-term therapy (which in several cases has been in the 15 year range so far). For the others, I check a BMD after 5 years, and if their BMD is worse than their initial one, I continue with the alendronate. And, the ones that I stop the alendronate in, I recheck their BMD in 2-3 years to make sure it is not deteriorating (my bias is that this is a pretty benign therapy overall, the functional/quality-of-life consequence of a hip fracture or a painful vertebral fracture can be quite significant, and, especially in a younger person with a long life expectancy, the further deterioration in BMD and increase in bone turnover markers on stopping the alendronate, as in the N Engl J Med trial, is concerning in the long-term even if no significant increase in these fractures happened in the next 5 years that they studied). The above Danish study was reassuring that long-term alendronate was associated with a continued 30% decrease risk of hip fracture and there was no increase in subtrochanteric and femoral shaft fractures
  • And, I will add my longstanding tirade that it is really important to down-titrate PPIs whenever possible, given the multitude of well-defined adverse effects including decrease in BMD/ 30% increase in fractures (in a large meta-analysis). I have found that most of my patients are able to downgrade to H2 blockers or calcium tablets, if not able to get off the meds completely

See https://stg-blogs.bmj.com/bmjebmspotlight/2016/01/28/primary-care-corner-with-geoffrey-modest-md-guidelines-on-length-of-bisphosphonate-therapy/ for the American Society for Bone and Mineral Research guidelines on the length of bisphosponate therapy, which goes into further depth on the randomized controlled trials, and is not so different from my assessment above, just that the Danish trial does give further reassurances for using longer-term bisphosphonates.

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