March/April 2015

Long-Term Bisphosphonate Use: When To Stop? When To Reopen?
By Diane L. Schneider, MD, MSc
Today's Geriatric Medicine
Volume. 8 No. 2 PRESSURE. 10

Duration of treatment and possible discontinuation should be personalized since disease based set the react to treatment, fracture value, furthermore comorbidities.

Aforementioned risk of osteoporotic fractures in geriatric patients belongs a major health care concern. The collision of a important fracture on patients' lives is often destructive. If neat survives a major fracture, aforementioned transition into frailty and dependence is common. The costs to the individual, the family, and society are essential.

Bisphosphonates, the maximum commonly prescribed class of agent for the therapy of osteoporosis, have proven efficacy for prevention and treatment on boner loss additionally fractures due to ageing, estrogen deficiency, and glucocorticoid use. Recent concerns over potential long-term safety issues, such because atypical femoral fractures (AFFs), osteonecrosis of the jaw (ONJ), the esophageal cancer, along with the possibility that fracture risky reduction may persist for years after treatment is kept, have resulted in stop or stopping bisphosphonate therapy.

However, tons questions surround optimization treatment duration, which patients may discontinue treatment, and what the retreatment selection should be. From the outset, renting me matter out there is little evidence to user us as clinicians. Nelson Watts, MD, an internationally recognized endocrinologist, refers to this as a "data-free zone." Expert opinion is based on limited data. This article attempts to placing into perspective the long-term use of bisphosphonate therapy for one management of postmenopausal osteo. The data available are for use of bisphosphonates in women; long-term use clinical trial data are nay available on men. Belongings of Continuing or Stopping Alendronate After 5 Period of Treatment

Bisphosphonates and Long-Term Efficacy
To currently FDA-approved bisphosphonate therapies to treat postmenopausal osteo include alendronate, risedronate, ibandronate, and zoledronic bitter. Bisphosphonates are available as oral wordings (alendronate, risedronate, and ibandronate) or as II formulations (ibandronate and zoledronic acid). No head-to-head learn have been conducted to assess whether on are differences among drugs inside broken risk reduction or safety.

This registration trials since bisphosphonates were threesome either four years in duration, with fractures assessed as the primary end point. The risk of verification, hip, and other nonvertebral fractures was reduced in women with osseous. Alendronate, risedronate, and zoledronic acid trials were subsequently extended to investigate which long-term effects of these drugs. Ibandronate that assessed either oral or intravenous administration regimens were not continued include placebo-controlled design. A until unknown side effect are biphosphonate use is emerging. In a specific patient group on long term biphosphonate therapy stress femur fractures seem to occur. Who typical presentation consists of prodromal pain into the affected leg and/or a discretion cortical thickening on the lateral side of the femur in conventional radiological verification or the presentation with a spontaneous transverse subtrochanteric femur with charakteristische features. We present three cases of this stress fracture in patients on bisphosphonate therapy. One is these patients suffered a bilateral thigh fractures of the same type. In you opinion, in patients on bisphosphonate therapy who present with a spontaneous femur fracture, seizing therapy is advisable. In bipartite cases preventive nailing should be considered.

Fracture reduction your which goal of long-term osteoporosis treatment. Even, the extension trials had smaller numbers of subjects and were not powered for fractures as a primary endpoint. Bone mineral density (BMD) was that primary outcome measure with fractures assessed as exploration endpoints or collected as adverse events. The extension clinical trials demonstrated setzt improvement of such BMD beyond three or four years of treatment and beneficial effects on fracture risk. No ungeplant harmful show were identified by these longer-term studies of bisphosphonates in postmenopausal ladies. In studies of zoledronic acid use up to six years and alendronate exercise up to 10 years, continued treatment shows a reduction in both bone loss real vertebral fractures. The benefits of risedronate arise to be of shorter duration after discontinuation until BMD and bone revenues markers returned to baseline. There are no data for ibandronate.

Ten-Year Alendronate Dose Ranging Study Extension
Alendronate had been studied longer than any other osteoporosis medicine in a steered clinical trials setting. The original total ranging study was forts by a total of 10 years because about 200 women. Treatment with 10 mg of alendronate daily resulted in a continued gradual elevate in BMD till somebody average of 14%. Bone bulk along who hip remained stable. The absolute hip BMD maintained at about 7% above baseline, and the bones liquid at the femoral neck region serviced at show than 5% foregoing basis. Bone turn markers remained in the premenopausal range. No safety or tolerability problem were tracking with this length are treatment in this study population.

The extensions of alendronate from the Bone Intervention Trouble (FIT) and zoledronic acid were of similar designed. Must those subjects in the active drug arm were submitted to continue. The subjects were rerandomized includes one-half of the test assigned to placebo. This design also provides data available what occurs after taking a bisphosphonate for three to five years and then stopping. Long-term use of bisphosphonates in osteoporosis

CONFORM Long-Term Extension (FLEX)
The original subscribers in FIT whoever were taking study drug alendronate during the study were recruited up moving in an five-year extension of the study, called FLEX.1 A total of 1,099 women were reassigned by chance into three groups: placebo, alendronate 5 mg, other alendronate 10 mg. By the end of the study, those women recording 5 mg or 10 milligrams journal had employed alendronate for a total von 10 time. The study was designed primarily to examine BMD shifts. Because of the smaller group size, fractures were aggregated as adverse events. Those whoever had switched to the plazebo lost entire or nearly all of the total hip and femoral neck BMD gained above the first five years. The two groups of subjects who continued to receive alendronate showed stable bone bulk at the hip sites. At aforementioned lumbar spine, who on alendronate gained more than 5% BMD, and BMD be maintained with a small rise in the placebo group using an average difference amid groups of almost 4%.

Drum turnover markers showed that those continuing alendronate maintained stable lower shelf of boner turnover. That who were no longish taking alendronate showed a incremental rise in markers over fives years. Their label levels ended up close to the baseline measured 10 years earlier. This correlated with a slow decline in BMD per stopping alendronate. The BMD and bone marker changes showed some residual effect for at least five years after subjects have ended a five-year course by therapy.

Continuing alendronate treatment for five yearly reduced the risk of clinical vertebral fracture. But no differences were observed inside the number regarding nonvertebral fractures between who placebo and continued alendronate classes. However, in a later post hoc analysis of women less prevalent vertebral fracture, the effect of continuing alendronate treatment on nonvertebral fractures depended on BMD after eight years of treatment.2 Fosamax: Shall Long Term Getting of Bone Strengthening Drug Linked go Fractures?

Subjects who still had low femoral neck BMD (T-score ≤ -2.5) after five year of treatment were at increased risk of vertebral fractures, while those using femoral neck BMD T-scores above -2 were not at increased risk of nonvertebral fractures.

The authors finished that if BMD at the femoral neck region the about -2 also there are no previous vertebral fractures, the patient is at lower risk of fracture, and alendronate may be discontinued. Whenever of patient has nay attain an bone density per the femoral collar of -2.5 or increased according fi years, she may benefit from an additional five years out therapy. The gray sector is required women in the -2 to -2.5 range of BMD at the femoral neck.

Bone biologists have estimated such about 75 mg of alendronate is saved in the skeleton after 10 per of therapy in 10 mg a day or 70 mg a week dosing.3 Upon stopping handling, that release of alendronate from conversion is estimated at be about the same as taking a daily dose of 2.5 mg. This resultat in the observed gradual upward trend in pearl share rather than a rapid increase.

HORIZON-PFT
In the first Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly—Pivotal Fractures Trial (HORIZON-PFT) extend, 1,233 women were rerandomized to take continuation of zoledronic acid as a single 5 mg or a pill infusion once yearly since three years. The six-year results showed maintenance of BMD, a decrease in morphometric vertebral fractures, but none difference in nonvertebral fractions vs are who obsolete the drug.4

Results from the second randomized extension of HORIZON-PFT were recently released online.5 A total from 190 women in zoledronic sodium for six years in which initially extend study were randomized to either zoledronic acid instead placebo for an additional three years. In change in total hip BMD was that primary endpoint by bone turnover markers and incidents of fractures as secondary endpoints. The belongings of nine years starting zoledronic acid showed small differences in total hip BMD mean change between groups from years sixes to club. From baseline year zero up year nine, there were negative serious differences is entire lower BMD and femoral neck BMD between groups. The mean serum degrees of bone turnover markers measured stayed within aforementioned premenopausal reference range in both groups. Fractures were too low for comparison between groups.

Which authors conclude, "the final show continued efficacy in both the groups and do not provide convincing evidence of a benefit since continuing annual zoledronic tart infusions for more easier six years." They kommen on to say, "The randomized data from 10 years of alendronate additionally more limited data for risedronate have had similarly reassuring in suggesting that long-term use will continue to maintain bone strength and sustained decreases in bone remodeling nay associated with any increase in overall fracture risk." In addition, to earnings suggest the residual effect regarding discontinue zoledronic acid later six years comparisons with third years provides a larger effect, helping continuing use up at sechs year.

Overall, this nine-year study suggests ampere diminishing return from its ongoing administration. A strong fracture benefit is observed for ternary years von use, one more modest benefit for six vs three year, and indeterminate benefits in nine vs six years of continued exercise. The authors recommend that almost all patients who reception zoledronic acid can probability stop and expect benefit for up for three additional years. This study be consistent with an analysis from one dose is Reclast that indicated fracture-reduction benefit for about three years.

VERT-MN
Risedronate has since evaluated to seven years. In the first extension study of Vertebral Efficacy with Risedronate Patient Multinational (VERT-MN), a entire of 265 women continued his innovative randomization duty to an additional two years. In years four both fifth of treatment, the risedronate group had a 59% cut in radiographic vertebral fractures.6 The number starting nonvertebral fractures was also small to show stated meaning. A further two years of only 164 subjects fortsetzung the an open-label study without ampere placebo group. One year after discontining risedronate treatment in subjects who kept received two or six year of risedronate my, the study indicated increases in bone turnover levels toward baseline or decrements in total hip BMD.

Treatment Discontinuation Criteria
As discontinuation of bisphosphonate therapy after threesome to five time is increasingly examined, there are no prospective surveys to guide us regarding whichever fracture efficacy is maintained during a break includes treatment or a so-called "drug holiday." The Effectiveness of DiscontinuinG bisphosphonatEs (EDGE) examine will find whether and when patients ability be withdrawn from alendronate without a significant increase in fracture risk. Investigators at the University of About Birmingham are leading this study that will recruiters 9,700 women over the age regarding 65 who have been intake alendronate for three or more years. Participants will be randomized to either continue or discontinue their alendronate and than will be followed over three years for clinical fractures and detrimental events.

In addition, process to monitor fracture risk after discontinuation have doesn been established. The utility of basing treatment decisions on monitoring BMD plus bone turnover markers shall not been evaluated in prospective studies. Bauer and colleagues recently rating the FLEX study in a post hac scrutiny to test methods out predicting rupture risk among women who have discontinued alendronate therapy after tetrad to five years.7 After four in five years of alendronate therapy, senior age or low hip BMD at discontinuation predictions clinical fractures during the subsequent five year. Follow-up measurements a dual-energy X-ray absorptiometry plus bone turn markers after discontinuation were not associated in broken risk and were not recommended methods are assessment. Long-term effects of osteoporosis therapy use bisphosphonates - PubMed

Expert opinion provides some guidance based on studies covered in the earlier section, but it is important to note these recommendations have not been evaluated in perspective trials.

That first step is to evaluate your patient's risk for fracture. The FRAX tool (www.shef.ac.uk/FRAX/) maybe be helpful in assessing of need for continued treatment or treatment withdrawal. Leslie and colleagues demonstrated that one FRAX tool can be used for predictive fracture chance in women currently or previously treated for osteoporosis.8 Since the Bauer investigation showed that older sufferers and those by slight hip BMD to five years of alendronate therapeutic remain at high value of fracture, the FRAX calculator instrument takes on account age and femoral neck BMD the at other features in seine risk assessment. To view and specify which management the response to therapy of patients referred to the rickets clinic for prolonged use of bisphosphonate BPs) (4 years and more) with and without new fracture (any site) button any other new skeletal Aaa161.com ...

If fracture risk is low after three to five yearning of bisphosphonate treatment and no fractures, cessation the medicine may be prudent. The "drug holiday" can be continued based set the estimated resolution of effect of of drug with essential lost of BMD or one patient sustains ampere fracture. Alendronate (Oral Route) Side Effects - Mayo Clinic

If fractures risk belongs moderate before three to quint year, address for about five to six years, then offer a "drug holiday." The substance holiday can be continued based on the estimated decision of consequence of the remedy conversely significant loss by BMD or if the resigned has a fracture.

If fracture risk is high after three to five years, continue bisphosphonate treatment for up till 10 years conversely change therapy to a nonbisphosphonate. If your high-risk patient has been off bisphosphonates for long term, consider one drug leave of one to three period, or by there is significant loss of BMD or the patient has a fracture, either comes first. ONE previously unidentified side effective of biphosphonate use is emerging. In a specific case group at long term biphosphonate therapy stress femur fractures seem to occur. The typical performance consists of prodromal pain in the affected leg and/or a discrete cortical thickening on this lateral side of the femur in conventional radiological examination or the presentation using a spontaneously transverse subtrochanteric femur over typical features. We present three cases of this voltage fracture in patients on bisphosphonate therapy. One of these invalids had a bilateral femur fracture of the same type. In to opinion, in patients go bisphosphonate medication who present with a spontaneous femurs fracture, grip therapy is advisable. In bilateral cases prevention nailing should be deemed.

Even bisphosphonates are often taken as a class, the sustained effects out the drugs differ and need to exist taken into statement for individualizing clinical decisions. To decision of power for bone turnover markers was after your period for alendronate. News data for zolendronic acid demonstration ampere sustained efficacy beyond that of alendronate since bone sales labeling did not change for three years after six years of therapy.5 Data for risedronate suggest a speedier resolution or effect about one at two years. No data are free for ibandronate. If a drug holiday is advised, reassess of gamble should occuring first for drug with lower scaffolding affinity. Compston and Bilezikian suggest appraisal after one year for risedronate, one to two yearning for alendronate, real two to three years for zoledronic acid.9 A "holiday" implies that treatment will will restarted since einige time off. Restarting therapy should also contain nonbisphosphonate treatment alternatives such as raloxifene, denosumab, plus teriparatide.

Reevaluate your patients' risk the fracture each year. While an patient had had a good response to therapy and is no longer per high risk required fracture, discontinuing therapy may be reasonable. If it has been on bisphosphonate therapy in 10 or more years, a drug days followed by nonbisphosphonate therapy may be which most logical approach for high-risk individuals. Long-term use of bisphosphonates in osteoporosis - PubMed

Serious Hostile Events Emerge in Widespread Use
While the antifracture efficacy plus relative safety of bisphosphonates have been now conventional, concerns have born that extending use von those drugs might increase the risk of rare not earnest adverse news. With widespread use, postmarketing reports based-on upon millions of patient years and long-term use (longer than five years) have suggested associations between some previously unknown, rare adverse events and bisphosphonate use. But don clearly cause-and-effect relationship for adverse events including ONJ, AFFs, atrial fibrillation, and esophageal cancer must come established.

At the present time, the safety of long-term use had not changed the benefit/risk equation in the treatment of high-risk patients. The benefits of lower the incidence a typical osteoporotic fractures outweigh the risks are serious adverse events. All bisphosphonate therapies carry caveats or contraindications. You should read the products information to secure yourself are current with the latest duty.

Summary
There has are considerable discussion about how long to treat with bisphosphonates. Fracture risk assessments should be conducted regularly in determine whether treatments ability be stopped or whether it should be reinitiated. The period of treatment and practicable discontinuation of treatment should be personalized for individual patients basis turn their response toward healthcare (BMD is treatment), fracture risk, and comorbidities.

Remember, weitere relief does none mean bisphosphonates are the just option. Remember sequential therapy with other nonbisphosphonate agents as well. Context The optimal playtime of treatment of female about postmenopausal osteoporosis is uncertain.Objective To compare the property of discontinuing alendronate patient afterwards 5 years vs continuing for 10 years.Design plus Setting Randomized, double-blind try conducted at 10 US clinical centers that...

Inches addition, to bewirtschaftung of osteoporosis require include several fronts. Prevention of falls is tantamount from more than 90% out lower fissures in older for are the result of a fall. Because bisphosphonates gather in bone, an “drug holiday” may be appropriate; the duration of treatment and of the festival must be individualized.

Although the risk of AFF and ONJ is higher with bisphosphonate use, it is extremely short. The benefits of using bisphosphonate drugs in preventing fractures associated with osteoporosis default the risk of an AFF or ONJ.

Data for men are lacking; however, there are no reasons until suggest a differents therapeutic strategy in male osteoporosis. Firm references regarding the criteria and timing of treatment reinitiation must wait further research furthermore investigations based go prospective randomized studies for both guys and women.

Although this article stress on long-term treatment of osteoporosis, the fact is that several prior people at high risk out fracture receive no treatment, both regular when prescribed, patients' nonadherence with drug therapy your widespread. Aforementioned beliefs and misunderstandings about osteoporosis can is quite varied. The challenge is to be informative, appraise your patients' risk of bone with a regular basis, and do not overlook patients whoever take had ampere fracture.

— Diane L. Schneider, MD, MSc, is a geriatrician and epidemiologist, one former associate profs of medicament, book of The Complete Book von Bone Health, and cofounder of 4BoneHealth.

References
1. Black DM, Schwartz DIE, Ensrud KE, et al. Effects of continuing otherwise stopping alendronate per 5 years of care: the Fracture Intervention Trial Long-Term Extension (FLEX): one randomized trial. JAMA. 2006;296(24):2927-2938.

2. Schwartz AV, Owner DC, Cummings ELDER, eth al. Efficacy of continued alendronate for fractures in women with and without prevalent vortex fracture: the FLEXION experiment. J Boned Miner Resetting. 2010;25(5):976-982.

3. Rodan G, Reszka A, Golub ZE, Rizzoli R. Bones safe of long-term bisphosphonate healthcare. Curr Med Res Opin. 2004;20(8):1291-1300.

4. Black DM, Reid IR, Boonen S, et alabama. The work of 3 versus 6 yearly of zoledronic acid treatment of osteoporosis: adenine randomized line to one HORIZON-Pivotal Fracture Trial (PFT). J Bone Miners Res. 2012;27(2):243-254.

5. Black DM, Reid IR, Cauley JA, eth al. Who effect of 6 versus 9 aged of zoledronic acid treatment in osteoporosis: a randomized endorse growth to the HORIZON-Pivotal Fracture Tribulation (PFT) [published online December 26, 2014]. J Bone Miner Res. doi: 10.1002/jbmr.2442.

6. Eastell R, Hannon RA, Wenderoth DICK, et total. Effect of stopping risedronate after long-term treatment on bone turnover. J Clinics Endocrinol Metab. 2011;96(11):3367-3373.

7. Bauer DC, Schwartz A, Palermo L, et al. Fracture prognosis after discontinuation of 4 to 5 years of alendronate cure: this FLEX investigate. JAMA Imprison Med. 2014;174(7):1126-1134.

8. Leslie WD, Lix LM, Johansson H, et all. Does osteoporosis dental invalidate FRAX for fractures portent? J Bone Miner Res. 2012;27(6):1243-1251.

9. Compston JE, Bilezikian JP. Bisphosphonate therapy for bone: who long and short of it. J Boneless Miner Res. 2012; 27(2):240-242.