Bisphosphonates (BP) are potent inhibitors of bone resorption that inhibit the activity of osteoclasts. All approved bisphosphonates have been shown to reduce vertebral fracture risk and increase BMD, whereas some have demonstrated reductions in non-vertebral and hip fracture risk as well.

They are available in oral and intravenous formulations, with weekly, monthly and annual dosing schedules, depending on the specific agent. Bisphosphponates bind to bone mineral, and consequently have a long skeletal retention. Orally administered BPs have a poor intestinal absorption and can induced mild intestinal disturbances.

Alendronate

Alendronate decreases bone resorption and formation markers, increases BMD and reduces the incidence of fractures by 30 to 50 % in women with established osteoporosis (1). The anti-fracture efficacy has been shown both in women with prevalent vertebral fractures and in women with low BMD (T-score<-2) but without vertebral fractures [1,2].

Meta-analysis carried out on the basis of several studies in postmenopausal and elderly osteoporotic women showed that alendronate decreases the risk of hip fracture by about 45 % [3]. Bridging studies showed that once-weekly alendronate at the dose of 70 mg is therapeutically equivalent to the reference daily regimen (similar increase in BMD, similar decrease in bone turnover marker (BTM) levels) [4]. In early postmenopausal women, a smaller dose of alendronate (5 mg) prevents bone loss [5].

In osteoporotic men, alendronate increases BMD at the lumbar spine and hip and decreases the incidence of vertebral fractures [6].

Alendronate also prevents bone loss in men receiving androgen deprivation therapy for prostate cancer [7] and is effective in the treatment of glucocorticoid-induced osteoporosis [8]. Rare cases of esophagitis have been reported. 

Risedronate

Risedronate decreases the incidence of new vertebral and peripheral fractures by the same extent as alendronate in women with low BMD and in women with prevalent vertebral fractures [9,10]. In osteoporotic women 70 to 79 years of age, risedronate decreased the incidence of hip fracture by 40 % [11]. Bridging studies showed that alternative doses of risedronate (35 mg once a week, 75 mg on two consecutive days a month, 150 mg once a month) decrease the BTM levels and increase BMD to a similar extent as the daily regimen [12-14]. Also in men with low BMD, risedronate decreased bone turnover and increased BMD [15]. The efficacy of risedronate has also been shown in the prevention and treatment of glucocorticoid -induced osteoporosis [16].

In a post-hoc analysis carried out in data combined from four phase III studies, risedronate reduced the incidence of fractures within 6 months of treatment [17]. Some [18], but not all [19], observational studies suggest that the anti-fracture efficacy of risedronate appears earlier than that of alendronate. However, these analyses are based on the retrospective analyses of the databases of the healthcare providers and no randomized head-to-head studies permitting direct comparisons were performed.

Ibandronate

Ibandronate is commercially available as an oral daily regimen (2.5 mg/day), oral monthly regimen (150 mg once monthly) and intravenous form (3 mg intravenously every 3 months). In postmenopausal osteoporotic women, oral ibandronate administered daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months) induced a rapid, pronounced and persistent decrease in bone turnover, increased BMD and reduced the incidence of vertebral fractures by at least 50 % [20,21]. Oral ibandronate administered at the dose of 150 mg once monthly induced a greater decrease in the BTM levels and a significantly greater increase in BMD than the daily ibandronate [22].

Once-monthly ibandronate (150 mg) also reduced the risk of vertebral fractures to a similar extent as weekly alendronate and risedronate [23]. In postmenopausal osteoporotic women, intravenous ibandronate (2 mg every 2 months or 3 mg every 3 months) induced a similar decrease in the BTM levels, a greater increase in BMD and a similar reduction in the incidence of clinical fractures in comparison with daily ibandronate [24].

Meta-analyses of the results of all the existing studies showed that the annual cumulative exposure (ACE) to ibandronate higher than 10.8 mg was associated with a decrease in the incidence of the non-vertebral fractures by about 30 to 40 % [25,26]. (Please note: calculation of ACE takes account of the intestinal absorption of a drug and corresponds to its quantity which is available to bone tissue.) In male cardiac transplant patients, ibandronate (2 mg i.v. every 3 months) decreased the BTM levels, prevented bone loss and reduced the incidence of vertebral fractures [27].

Zoledronic acid

Zoledronic acid administered intravenously to postmenopausal women with osteoporosis at a dose of 5 mg once-yearly induced a sustained decrease in bone turnover, a progressive increase in BMD and a significant decrease in the incidence of vertebral fractures by 70 % and in the incidence of non-vertebral fractures by 25 % (including a significant 40 % decrease in the incidence of hip fractures) [28].

In older men and women with recent low trauma hip fracture (two weeks or later but less than 90 days after surgical repair) zoledronic acid increased BMD at the hip, decreased the incidence of clinical fractures (including a significant decrease in the incidence of hip fracture) and reduced the mortality rate by about 30 % [29,30]. In men and women treated with oral glucocorticoids, zoledronic acid induced a greater decrease in the rate of bone turnover and a greater increase in BMD compared with risedronate [31]. In men receiving androgen deprivation therapy for prostate cancer, zoledronate slowed bone turnover and prevented bone loss [32].

Possible side effects and limitations of bisphosphonates

Recently, several issues related to long-term use of BPs have been raised. An important and associated question is how long patients should be treated with BPs? BPs are potent suppressors of bone resorption and may lead to a phenomenon called “severely suppressed bone turnover” [33], particularly in patients on glucocorticoid therapy and/or concommitent anti-resorptive therapy, such as HRT. Such extreme inhibition of bone remodeling may theoretically lead to an accumulation of microdamage which might compromise bone strength and increase the risk of low trauma fracture or delay fracture healing [33-35]. However, iliac crest biopsies from women on long-term bisphosphonate do not show increased microdamage [36], and clinical trials of bisphophonates did not show evidence of altered healing.

To avoid potential side effects, many clinicians consider it apropriate to re-evalute the patients fracture risk after 5 years of treatment, and then consider whether to stop or continue the treatment. There is limited evidence to support this key clinical decision. In the FLEX trial, withdrawal of alendronate after 5 years of treatment was followed by a mild decrease in BMD (at some, but not all sites) and a mild increase in BTM levels [37,38].

In another study, fracture incidence after BP discontinuation increased in women who took BPs for 2 years with a suboptimal adherence [39]. By contrast, after discontinuation of the long term treatment with alendronate in the FLEX study, fracture incidence remained reduced for 5 years, except for a slightly higher risk of clinical vertebral fractures in comparison with women who took alendronate continuously [37]. However, there was no placebo group in this study, so it is difficult to draw firm conclusions. Thus, there are no evidence-based guidelines how long osteoporotic patients should take BPs. However, on the basis of the available clinical and pre-clinical data, it can be inferred that, in the vast majority of patients, stopping therapy is more likely to do harm than continuing therapy [40].

Osteonecrosis of the jaw (ONJ) is observed in patients with various malignancies who are treated for a long period of time with high doses of BPs [41,42]. By contrast, cases of ONJ in the osteoporotic patients are extremely rare – no case was found in more than 3000 patients participating in the clinical trials with zoledronate and alendronate [28,29,37] and no causal link between ONJ and BP therapy in these patients has been convincingly demonstrated. Precipitating factors for ONJ, which occurs in people who have never received BP therapy, include dental surgery, ill-fitted dental prosthesis and aggravating factors (heavy smoking, infection) [43-45]. Clinical data do not support the use of BTM (e.g. serum CTX-I concentration) as predictors of the risk of ONJ in the bisphosphonate-treated patients [46].

Recent case reports have suggested a higher occurrence of atypical femoral shaft fractures (subtrochanteric or proximal diaphyseal fracture) in a select group of women and men treated long-term with alendronate, particularly in those receiving glucocorticoids and/or another anti-resorptive medication such as estrogen (47-52). It is not clear if these fractures are related to long-term alendronate treatment or rather are a form of fragility fracture in osteoporotic patients. These fractures are generally thought to be low trauma fractures occurring in patients who have taken alendronate for several years (usually > 5).

Prior to their fracture, these patients often, but not always, had experienced persistent pain in the thigh that was, aggravated during standing and resistant to analgesics. Individuals with these types of fractures appear to have modest cortical thickening of the femur diaphysis, and bone scintigraphy shows increased uptake of the radioisotope in the subtrochanteric area at the site of the cortical thickening which can be bilateral, and which is consistent with a stress fracture.

From the practical point of view, two points are important. Firstly, a pain in the thigh not related to trauma and aggravating during standing needs further investigation when it is reported by a patient treated with alendronate. Secondly, it is advisable to discontinue alendronate in patients with normal BMD values on long-term glucocorticoid treatment. Obviously, these suggestions are always true, but particularly relevant in the context of the femoral shaft fractures. Additional studies are needed to determine the mechansims underlying these fractures and the characteristics of the few patients that may be at increased risk for this injury.

Treatment with BPs was associated with higher risk of atrial fibrillation in some [28,53,54], but not all [55,56], studies. The association between use of BPs and risk of atrial arrhythmia and its clinical significance remains to be elucidated. Women treated for osteoporosis may have a higher cardiovascular risk before the beginning of the BP treatment than non-osteoporotic women. During treatment with zoledronate, electrolyte imbalance does not seem to precipitate the atrial arrhythmia, because episodes of atrial fibrillation did not cluster in time after infusions, when serum electrolytes are most affected [28].

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