However, this report lacked information regarding risk factors for esophageal cancer in this group of patients and the expected incidence of esophageal cancer in this age group Furthermore, it was limited by the lack of a control group, which makes the association between esophageal cancer and bisphosphonate use purely speculative Two other reports, one using data from European national registries and the second from the U.
Medicare database, have not shown an increased risk of esophageal cancer among individuals who were receiving oral bisphosphonates compared with those who were not 43 , Lastly, the time from exposure to diagnosis was brief and hence not consistent with a causal relationship 45 , The theoretical rationale for a possible association of esophageal cancer and bisphosphonate use stems from the fact that this class of medications can cause erosive esophagitis, and esophageal biopsies of patients on alendronate have revealed crystalline material similar to this drug as well as persistent mucosal abnormalities 47 , Although further studies looking at the potential risk for carcinogenicity are clearly needed, the current data do not support a causal association between oral bisphosphonates and esophageal carcinoma.
The prescribing information for all bisphosphonates lists musculoskeletal pain as a potential, albeit an uncommon, adverse effect. Although symptoms improved promptly in some patients after discontinuation of the offending drug, most patients experienced a gradual or incomplete resolution of symptoms The mechanism for this adverse effect is not known, and evidence supporting a causal relationship between this and bisphosphonate use is lacking.
Musculoskeletal pain is a common problem in this age group. Further studies are needed to evaluate the frequency and possible risk factors for this problem. Particularly severe musculoskeletal pain associated with bisphosphonate therapy has been described in patients with cystic fibrosis 50 and can be alleviated by prior glucocorticoid therapy At present, the FDA recommends instructing patients to alert their physician if such symptoms occur for consideration of stopping the medication.
Attempts have been made to analyze data retrospectively and shed some light in this area. Compared with placebo, there was no difference in the incidence of adverse events in the treatment groups regardless of renal function, and therapy was as effective in terms of preservation of BMD and reduction of fractures.
A retrospective analysis of the FIT data revealed similar findings with the use of alendronate Transient changes in renal function may occur in postmenopausal women after receiving iv zoledronate, but renal function returns to baseline in the long term Adverse effects on renal function seem to be primarily related to the peak concentration determined by the dose and the infusion rate.
Thus, bisphosphonates appear to be safe and effective in individuals with modestly reduced renal function. The low risk of kidney damage in patients receiving iv bisphosphonates can be reduced further by adequate hydration and prolonging the infusion rate.
No dosage adjustment is necessary in patients with mild or moderate renal impairment. However, there are inadequate data in patients with more severe chronic kidney disease and in end-stage renal failure, in which other forms of metabolic bone disease may be present This approach is mainly based on the known pharmacokinetics of bisphosphonates in subjects with normal renal function Although bisphosphonates reduce the rates of fractures due to osteoporosis, recent reports suggested a link between bisphosphonate use and the development of atypical insufficiency fractures.
This is thought to be due to long term oversuppression of bone turnover leading to impaired bone remodeling, accumulation of microdamage in bone and increased skeletal fragility 61— A number of case reports have described unusual low-energy subtrochanteric femoral fractures and pelvic insufficiency fractures, which exhibited problems with healing, in patients on long term bisphosphonate therapy 65— These fractures are typically associated with prodromal pain in the region of the fracture and are frequently bilateral; characteristic radiographic findings include cortical hypertrophy, a transverse fracture pattern, and medial cortical spiking Fig.
Bone biopsies in such patients often show severely suppressed bone turnover 59—61 , although we have seen a patient with one of these subtrochanteric fractures whose iliac crest biopsy was completely normal Watts, N. Several retrospective studies also suggested an association between bisphosphonate use and atypical fractures 74— On the other hand, a register-based national cohort study from Denmark showed that the ratio of classical to atypical hip fractures was identical in the alendronate-treated subjects vs.
This suggested that these atypical fractures were more likely due to osteoporosis rather than the bisphosphonate therapy itself. The observed association between long-term bisphosphonate use and atypical fractures does not prove causality, and additional large-scale studies are needed to elucidate this issue further. More definitive data would be critical because this may influence decisions regarding duration of therapy in selected individuals 78 , but concern about oversuppression of bone turnover resulting in atypical fractures should not lead to stopping bisphosphonate therapy in the vast majority of postmenopausal women at the present time 79 , X-rays showing an impending femoral shaft fracture A and a representative atypical diaphyseal femoral fracture B with thickened cortices and a beak or spike.
Lane and A. Approval of bisphosphonates in the United States was based on studies of 3 or 4 yr duration. Some of these studies have been extended, with two alendronate cohorts followed up for 10 yr 3 , 4 and risedronate cohorts followed up for 4 81 and 7 yr No new safety concerns have emerged.
Although some have expressed concern about possible oversuppression of bone turnover, iliac crest biopsies after up to 10 yr of treatment have not shown oversuppression. There has been considerable discussion about how long to treat with bisphosphonates.
This does not come up with treatments for other silent diseases such as hypertension and hyperlipidemia because it is well known that benefits of treatment disappear fairly quickly when treatment is stopped. It is a reasonable question when considering bisphosphonate therapy, however, because these drugs accumulate in the skeleton, leading to a reservoir that continues to be released for months or years after treatment is stopped As previously mentioned, the skeletal binding sites for bisphosphonates are virtually unsaturable, so a considerable amount could be accumulated.
Because release depends in part on the level of bone turnover, which is reduced by the presence of bisphosphonates, the actual amount released may be fairly small. Stopping alendronate after 10 yr of treatment at a dose of 10 mg daily which should be the same as 70 mg weekly , the amount of alendronate released from bone over the next several months or years would be equivalent to taking one fourth of the usual dose 2.
Earlier studies suggested that lower-than-standard doses of bisphosphonates might reduce the risk of fracture [alendronate 5 mg daily 85 , 86 and risedronate 2. When treatment is stopped, if there is continued presence of bisphosphonate in bone and continued release and possible reattachment to bone , there might be some lingering antifracture effect after treatment is stopped.
The extension of the risedronate Vertebral Efficacy with Risedronate Therapy-NA study was a 1-yr follow-up of subjects who completed 3 yr of blinded therapy with risedronate 5 mg daily or placebo and then stopped their study medications but continued calcium and vitamin D. The extension of the alendronate Fracture Intervention Trial enrolled subjects who had approximately 5 yr of alendronate treatment in the FIT into a second 5-yr study during which some subjects continued alendronate and others were changed to placebo.
The data suggest to us that, although there is some residual benefit in terms of fracture reduction for some time after a 3- to 5-yr course of bisphosphonate therapy, continuing treatment for 10 yr is better for some patients. Although the risks of bisphosphonate therapy for osteoporosis are small, for patients at low risk of fracture, the risk to benefit ratio may be negative. For patients who were candidates for treatment, after a course of some years, treatment may be stopped for a drug holiday.
Although it is difficult to find evidence to support the need for or clinical results of a course of treatment followed by a drug holiday how long to treat, how long the holiday should be, when the holiday should be stopped, effectiveness of treatment after restarting , we believe there is logic to support the following clinical scenarios as shown in Table 5 : 1.
Low risk of fracture: treatment is not needed. Treatment was not indicated in the first place and can be discontinued. Mild risk of fracture: treat with bisphosphonate for 3—5 yr and then stop.
The drug holiday can be continued until there is significant loss of BMD i. Treatment was indicated, but after 5 yr of treatment, a drug holiday might be considered. Moderate risk of fracture: treat with bisphosphonate for 5—10 yr, offer a drug holiday of 3—5 yr or until there is significant loss of BMD or the patient has a fracture, whichever comes first. Treatment was indicated, but after 8 yr of treatment, a drug holiday might be considered.
High risk of fracture: treat with bisphosphonate for 10 yr, offer a drug holiday of 1—2 yr until there is significant loss of BMD or the patient has a fracture, whichever comes first. A nonbisphosphonate treatment e. After 10 yr, she remains at high risk of fracture. If a holiday from the bisphosphonate is considered, interval treatment with teriparatide or raloxifene would be prudent.
Longer holidays might be appropriate for patients treated with bisphosphonates that bind most strongly to bone i. It has been suggested that a decrease in BMD or increase in bone turnover marker might be used to decide when to end a drug holiday, but the risedronate study showed that fracture risk remained reduced despite what appeared to be unfavorable changes in these parameters Conversely, there is no evidence that, off treatment, fracture risk is reduced if BMD is stable or bone turnover marker is low.
Bisphosphonates offer a safe and effective treatment to reduce fracture risk, with evidence for broad spectrum i. They can be administered orally daily, weekly, or monthly or iv quarterly or yearly. Since their initial introduction in the United States in , questions have been raised about their association with possible side effects ONJ, musculoskeletal pain, atrial fibrillation, atypical fractures, esophageal cancer that appear to be rare and may not be causally related.
For most patients with osteoporosis, the benefits of treatment outweigh the risks. Because bisphosphonates are avidly bound to bone, a reservoir of drug accumulates after years of treatment that is gradually released over months or years and appears to result in a lingering antifracture benefit for some time after therapy is stopped.
This makes it possible to consider drug holidays [time off bisphosphonate therapy but possibly on another agent ] and then resuming therapy. Although there is no strong science to guide us, we believe that some time off treatment should be offered to most patients on long-term bisphosphonate therapy. The duration of treatment and the length of the holiday should be tailored to individual patient circumstances, including the risk of fracture and the binding affinity of the particular bisphosphonate used.
Disclosure Summary: N. Watts NB Bisphosphonate treatment for osteoporosis. In: Avioli LV, ed. The osteoporotic syndrome. San Diego: Academic Press; — Google Scholar. Osteoporos Int 19 : — N Engl J Med : — JAMA : — J Bone Miner Res 12 : — Bone 24 : 73S — 79S.
Calcif Tissue Int 41 : — Lancet 2 : 42 — Drug Saf 21 : — Endocr Pract 12 : 48 — J Bone Miner Res 20 : — J Bone Miner Res 22 : — Marx RE Pamidronate Aredia and zoledronate Zometa induced avascular necrosis of the jaws: a growing epidemic.
J Oral Maxillofac Surg 61 : — Letter. J Oral Maxillofac Surg 62 : — Ann Intern Med : — Kolata G Drug for bones is newly linked to jaw disease. New York Times , June 2 , ;. Google Preview. Rubin R Drug linked to death of jawbone. USA Today.
Knox R Side effects noted with bone-loss drugs. N Engl J Med : The risk of vertebral, hip, and other nonvertebral fractures was reduced in women with osteoporosis. Alendronate, risedronate, and zoledronic acid trials were subsequently extended to investigate the long-term effects of these drugs.
Ibandronate that assessed either oral or intravenous dosing regimens was not continued in placebo-controlled design. Fracture reduction is the goal of long-term osteoporosis treatment. However, the extension trials had smaller numbers of subjects and were not powered for fractures as a primary endpoint. Bone mineral density BMD was the primary outcome measure with fractures assessed as exploratory endpoints or collected as adverse events.
The extension clinical trials demonstrated continued improvement of that BMD beyond three or four years of treatment and beneficial effects on fracture risk. No unexpected adverse events were identified in these longer-term studies of bisphosphonates in postmenopausal women.
In studies of zoledronic acid use up to six years and alendronate use up to 10 years, continued treatment showed a reduction in both bone loss and vertebral fractures. The benefits of risedronate appear to be of shorter duration after discontinuation until BMD and bone turnover markers returned to baseline. There are no data for ibandronate. Ten-Year Alendronate Dose Ranging Study Extension Alendronate has been studied longer than any other osteoporosis medicine in a controlled clinical trials setting.
The original dose ranging study was continued for a total of 10 years with about women. Bone density at the hip remained stable. Bone turnover markers remained in the premenopausal range. No safety or tolerability issues were observed with this length of treatment in this study population.
Only those subjects in the active drug arm were offered to continue. The subjects were rerandomized with one-half of the subjects assigned to placebo. This design also provides data for what occurs after taking a bisphosphonate for three to five years and then stopping. By the end of the study, those women taking 5 mg or 10 mg daily had used alendronate for a total of 10 years. The study was designed primarily to examine BMD changes. Because of the smaller group size, fractures were collected as adverse events.
Those who had switched to the placebo lost all or nearly all of the total hip and femoral neck BMD gained over the first five years. The two groups of subjects who continued to receive alendronate showed stable bone density at the hip sites.
Bone turnover markers showed that those continuing alendronate maintained stable lower levels of bone turnover. Those who were no longer taking alendronate showed a gradual rise in markers over five years.
Their marker levels ended up close to the baseline measured 10 years earlier. This correlated with a slow decline in BMD after stopping alendronate. The BMD and bone marker changes showed some residual effect for at least five years after subjects had ended a five-year course of therapy. Continuing alendronate treatment for five years reduced the risk of clinical vertebral fracture.
Determination of which route is best for a given patient should be based on individual patient factors, such as tolerance and adherence. A few researchers have compared the two routes for safety and efficacy. Most recently, [ 17 ] performed a meta-analysis of 17 studies comparing the safety and efficacy of oral alendronate and intravenous zoledronate.
Comparisons were done by specific fracture risk, for hip, vertebrae, and wrist. While the overall fracture risk reduction is nearly equal, [ 17 ] found that for prevention of vertebral fractures intravenous therapy, zoledronate, may be more effective in preventing vertebral fractures. The efficacy and safety of oral daily risedronate versus intravenous ibandronate were also investigated in a randomized double-blind study by [ 15 ].
Researchers concluded that intravenous ibandronate was equally efficacious to oral therapy, risedronate for new or worsening vertebral fracture over 3 years. Of note the findings were dose dependent. The aging population worldwide has caused an increasing economic burden upon society, related to health issues, osteoporosis being one facet. Hip fractures result in increased morbidity resulting in increased cost to the health care system as well as the individual.
Thus ensuring health care spending is prudent related to osteoporosis treatments and fracture prevention is significant. A strategy for cost-saving has been to consider withholding treatments that may not be cost effective for certain groups, commonly those with shorter life expectancies. The investigators found an increased cost effectiveness for older ages, even the extremes of old age, up to age 90 for initiating treatment, when treating osteoporosis in women for 5 years with oral bisphosphonates.
When considering cost treatment with bisphosphonates against cost of an acute hip fracture in the first year and possible long term care costs, researchers found that treatment with an oral bisphosphonate for 5 years was cost effective for all women without a history of hip fracture, irrespective of quartile of life expectancy.
Consequently, advanced age should not prevent consideration of osteoporosis treatment based on cost effectiveness. While withholding treatments in those with shorter life expectancies is the current recommendation, specific criteria as to qualifying as a shorter life expectancy has not been determined. In this analysis by [ 24 ] treatment with zoledronic acid in cognitively impaired patients with a life expectancy of just six months or more was found to be worthwhile.
While this was just one study, the growing population of cognitively impaired elderly is growing, making confirmation of this data valuable for the future treatment of this population [ 24 ].
Researchers have studied the question of cost versus benefits of bisphosphonate therapy in terms of medication costs. Concerns have arisen about atypical subtrochanteric femur fractures related to long-term bisphosphonate use, typically greater than 5 years [ 26 ]. It has been hypothesized that this prolonged and severe suppression of bone turnover may have negative effects by causing accumulation of microdamage and localized highly mineralized bone.
This may potentially increase the risk of stress fractures with normal activities and no known trauma [ 19 ]. Several reviews of atypical fracture found the average median length of treatment to be around five years with a range from years and increased risk with glucocorticoid use [ 19 , 27 ]. Due to the concern of atypical fracture, a task force was appointed by the American Society of Bone and Mineral Research to review this important concern.
The group concluded that long-term bisphosphonate use does increase the relative risk of atypical fractures; however, the absolute risk is low. The risk for atypical fracture may rise with duration of bisphosphonate exposure of greater than three years.
When an atypical fracture has been diagnosed, the bisphosphonate should be stopped to decrease the risk of atypical fracture in the opposite leg [ 28 ]. Patients with atypical fractures commonly present with unilateral or bilateral dull or aching pain in the groin or thigh. The time from the onset of pain to the time of diagnosis is usually weeks [ 29 ].
For a patient taking a bisphosphonate greater than 5 years or who is taking a concomitant glucocorticoid or PPI, an x-ray should be ordered. When a Proton Pump Inhibitor PPI is prescribed in conjunction with a bisphosphonate in the elderly population, the patient could be at increased risk for atypical fracture.
Proton pump inhibitors interfere with the absorption of calcium and bisphosphonates thus affecting their anti-fracture efficacy and have been incriminated in osteoporotic fractures [ 30 ]. As referenced above, glucocorticoids used concomitantly also place a patient at increased risk due to suppression of bone turnover" [ 26 ].
Case reports and case series have associated Osteonecrosis of the Jaw ONJ with patients taking bisphosphonates compared to those who have not been on bisphosphonates.
Bisphosphonates have a long half-life following cessation and may be associated with delayed healing and even the devastating complication of ONJ. Treatment with bisphosphonates may exert an inhibitory effect on oral epithelial growth. Prior to initiating bisphosphonate therapy, a dental review should be completed so any invasive dental procedures can be performed before the bisphosphonate is started. Patients should be instructed to promptly report any new dental symptoms, especially dental pain, swelling or exposed bone [ 31 ].
The risk of developing ONJ with oral bisphosphonate use is low but is substantially greater for patients receiving IV bisphosphonate therapy, particularly for metastatic cancer to the bone. The adverse effects vary by drug and patient physiology with the most common adverse effects being gastrointestinal; specifically reflux, esophagitis, and esophageal ulcers.
The gastrointestinal toxicity of oral bisphosphonates is likely to be a local, rather than systemic effect and is often related to taking the medication incorrectly. If a patient reports gastrointestinal intolerance to alendronate, risedronate may have fewer side effects. In clinical trials, the incidence of gastrointestinal side effects associated with risedronate was not different from placebo [ 6 ].
Intravenous pamidronate may be a good alternative for oral bisphosphonates for patients with gastrointestinal intolerance during treatment with oral bisphosphonates [ 32 ]. Intravenous Zoledronic Acid ZA 5 mg is associated with an increased incidence of pyrexia, myalgia, and influenza-like illness within three days of infusion when compared to placebo [ 4 ]. Adverse reactions following transfusion of zoledronic acid may be contributed to a rapid release of pro-inflammatory cytokines from circulating T cells which occurs most commonly after the initial dose.
Also, prior to each ZA infusion, clinicians should measure serum creatinine and ensure adequate hydration to prevent renal impairment or acute renal injury [ 6 ]. Adverse effects from bisphosphonates are not unusual, but rarely cause the need to discontinue the medication. The percentage of discontinuation with zoledronic acid was 2.
Request Appointment. Osteoporosis: How long must I take bisphosphonates? Products and services. How long must I take bisphosphonates for osteoporosis? Are they a lifelong commitment? Answer From Ann Kearns, M. Thank you for Subscribing Our Housecall e-newsletter will keep you up-to-date on the latest health information.
Please try again. Something went wrong on our side, please try again. Show references Rosen HN. Bisphosphonate therapy for the treatment of osteoporosis. Accessed June 9, Merck Manual Professional Version.
Accessed June 3, Kellerman RD, et al.
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