Primary Care Corner with Geoffrey Modest MD: Guidelines on Length of Bisphosphonate Therapy

By Dr. Geoffrey Modest

A not infrequent question in primary care is when to stop bisphosphonates (BPs) for women with osteoporosis. There was a recent guideline on this subject from a task force of the American Society for Bone and Mineral Research (see DOI: 10.1002/jbmr.2708, as well as doi: 10.1056/nejmp1202619 for the 2012 response by the FDA).

Details of their recommendations:

• Background:
  • Osteoporotic fractures are really common (they quote the stark but I suspect inaccurate frequency of 1 fracture every 3 seconds around the world…), with substantial morbidity and mortality
  • ​1 in 3 women and 1 in 5 men experience a fragility fracture after age 50
  • ​3-4 year studies confirm that BPs work in decreasing the risk of vertebral (40-70%), hip (20-50%) and nonvertebral (15-39%) fractures
  • Lots of people take them: from 2005-9, 150 million scripts were dispensed in the US
  • ​But, not so shockingly, these drugs are not benign, with reports of jaw osteonecrosis (esp in those on very high doses for cancer therapy, though unclear that increased duration of BPs lead to increased risk), and atypical femoral fractures often after minimal or no known trauma (still a pretty uncommon event: increasing from 3.2-50/100K person-years in the general population to double that with median duration of 7 years of BP use, with likely relationship with increased length of BP use). In 2010, the FDA added these atypical femoral fractures to the “warnings and precautions” of BPs.
• The data (from 2 studies with at least 5 years of treatment):
  • FLEX study (see JAMA 2006;296(24):2927)
    • 1099 postmenopausal women (mean age 73, 96% white, mean T-score was -1.9 for hip and -2.2 for femoral neck who had taken alendronate for 4-5 years were randomized to continue alendronate at 5mg/d, 10mg/d, or placebo. 60% had had a clinical fracture after age 45 and 1/3 had had a vertebral fracture. But those with hip bone mineral density (BMD) T-score worse than -3.5 or those with lower BMD than at baseline were excluded.
    • After 5 more years of follow-up, those who took either 5 or 10mg of alendronate had significantly less bone loss than those on placebo (e.g., femoral neck BMD improved 0.46% vs decreased 1.48% on placebo). But non-spine fracture risk was similar and there was not enough statistical power to assess nonvertebral fractures. And, another post hoc analysis found that there were increasing clinical fractures as both the femoral neck and total hip T-score were lower (going from <10% to 30% from the lowest to highest tertiles) in those who stopped the alendronate.
    • A subgroup analysis found that there was a reduction of nonspine fractures in women who did not have a baseline vertebral fracture and had a femoral neck T-score worse than -2.5
    • As an interesting aside in the FLEX trial, there was no evidence that monitoring bone-turnover markers (e.g. serum procollagen type 1 N-terminal peptide, C-terminal cross-linking telopeptide, or bone-specific alkaline phosphatase) predicted bone loss over the 5-year treatment-free period (i.e., there seems to be no basis for monitoring these markers in order to risk stratify women for future fractures).
  • HORIZON study
    • ​1233 postmenopausal women (mean age 75.5, 95% from Western populations, 5% Asian, mean femoral neck T=-2.6. 60% had at least one prevalent vertebral fracture) who had received 3 annual IV infusions of zoledronic acid, then either continued that for 3 more years or got placebo
    • ​Those on placebo had more femoral neck bone loss (-0.80 vs +0.24). those on continued zoledronic acid had fewer morphometic spine fractures (i.e., looking at vertebral dimensions), but no difference in nonspine or hip fractures (again, low statistical power for these outcomes)

• Some of their other points:
  • If one measures the suppression of markers of bone turnover (as a surrogate for BP efficacy), it seems that suppression persists for 2-3 years after stopping alendronate, and at least 3 years for zolendronic acid (though for ibandronate and risedronate, it lasts only 1-2 years)
  • In lower risk women (e.g. hip T-score better than -2.5), it may be reasonable to stop alendronate after 5 years, but monitor the BMD after an additional 2-3 years, and perhaps sooner after risedronate, since there tends to be a quicker rebound of bone-turnover markers (i.e., though these markers did not help in the FLEX study after 5 years of alendronate, they are predictive in those never on BPs, and without any data on long-term risedronate and stopping the med, I agree that it would be prudent to reassess them sooner)
  • ​Stopping BP treatment: minimal data, but suggestive that risk of atypical femoral fractures seems to decrease one year after stopping BPs [and, given the long-terminal half-life of BPs, the American Dental and oral/maxillofacial surgeon societies do NOT recommend discontinuing BPs for dental procedures, contrary to what I see in clinical practice in Boston. Though it is reasonable to delay initiating BPs if there is impending dental surgery]
  • There are small studies/reports finding that by using teriparatide therapy, there is healing of the atypical femoral fractures and jaw osteonecrosis

Their recommendations:

• After 5 years of oral BPs (3 years with IV), assess whether there were hip, spine, or multiple other osteoporotic fractures. If so, consider continuing therapy and reassess every 2-3 years
• If no intervening fractures, check the hip BMD. If better than T-score of -2.5, consider drug holiday and reassess in 2-3 years
• If hip T-score worse than -2.5 or patient considered high fracture risk (older than 70-75, other strong fracture risk, or high FRAX score), consider continuing BPs for up to 10 years, but reassess every 2-3 years

So, I basically support these guidelines. My reading of the literature is pretty much in agreement with this (despite the fact that of 15 members of the committee involved in these recommendations, 11 had drug company ties), and rechecking the BMD after 5 years before considering stopping meds. A few points:

• Since the cutpoint for enrollment in the FLEX study was a T score of better than -3.5 and no deterioration of BMD after being on meds for 5, I have used a T-score of roughly -3 or so as the cutpoint of when I stopped the alendronate, or if the BMD deteriorated. This current recommendation is more stringent, with a cutpoint of -2.5, which I think is related to the post hoc analyses showing that the worse the BMD, the more likely a fracture in those off the alendronate after 5 years.
• One thing to keep in mind in dealing with osteoporosis is that BMD is a quantitative assessment of the amount of mineralization of the bones and reveals nothing about the internal, qualitative structure of the bone, which clearly is very important in terms of the structural integrity of the bone. So, people can have fragility fractures even with normal BMD, and there are no data I have seen suggesting that a woman with a fracture should stop the BPs at five years, even with a non-osteoporotic BMD.

Other issues:

• What about women with really bad BMD (worse than -3.5) and excluded from the studies? It seems reasonable to me to check the BMD after a couple of years (to make sure their BMD is not deteriorating and that they might benefit from more aggressive therapy, e.g. with denosumab, etc.) if BMD is okay, could check again after 5+ years, though my guess is that pretty much all of these women will need prolonged therapy (and, they should be worked-up for secondary causes of osteoporosis…).
• What to do if patient at high fracture risk and on BPs for 10 yrs? These guidelines stop at 10 years because there are NO data for longer treatment. Given the lack of incremental adverse events when going from 5 to 10 years in the FLEX study, the benefits of continuing BP therapy may well outweigh the likely (though unknown) risks.
• What if they are on meds that increase fracture risk (e.g. steroids, aromatase inhibitors)? Studies suggest that the increased fracture risk for steroids is partially independent of the steroid effect on BMD. Again, no data, but seems to me that prolonged BP therapy may be reasonable. On stopping steroids, there are data that fracture risk is reduced, but unclear that it returns to baseline risk.
• What if the patients are at high risk because of prior fractures? These patients remain at high risk of future fractures. Again, no long-term data, but prolonged therapy (i.e., >10 years) may well be appropriate.
• What is the appropriate dose of BPs after 5 years? One intriguing possibility (not discussed anywhere I have seen) is reverting to a lower dose of alendronate. The FLEX study found that the equivalent of 35mg/week of alendronate had the same results 5 years later than the 70mg/week dose. What about using the lower dose after 5 years?
• What is the generalizability of this recommendation to non-white women?  For example, Black Americans have significant differences in vitamin D binding protein (see N Engl J Med 2013;369:1991).
• What about men? Studies are mostly 2-3 years in length. And fractures have not been the primary endpoints. (There is no evidence that there is a reduction of nonvertebral or hip fractures in men). And no data on long-term safety of these meds in men (and no data finding osteonecrosis or atypical femoral fractures). Despite the lack of data, osteoporosis and especially hip fractures are about as common in elderly men as women, so my sense is that it is reasonable to treat men as women for osteoporosis at this point.

So, my bottom line is that I would probably err to over-treating most women at significant risk of fracture and will probably adopt these recommendations with the T -2.5 as the cutpoint. My primary reason is that the 10 year FLEX study did not find any increases in adverse effects of continued alendronate (and there are even some observational data suggesting lower incidence of breast, colon, and gastric cancers, and even cardiovascular disease and mortality); therefore, it seems to me that the risk of fracture, even a vertebral fracture (1/3 of which can cause chronic pain and disability), and likely (though not proven) decreased likelihood of hip fractures in the more distant future (i.e., BMD is higher in the hip with continued alendronate) seem to outweigh the risks from the evidence so far. And, for people at continued high fracture risk at the 10 year mark of BP therapy, I would strongly consider continuing that therapy.