Evidence for Using Alendronate to Treat Adult Avascular Necrosis of the Femoral Head: A Systematic Review

Background

SHORT-TERM OUTCOMES ANALYSIS:

Agarwala et al. [18] studied 16 patients with AVN of the femoral head – most of them secondary to the use of corticosteroids. They used a regimen of alendronate 10 mg/day + calcium 1 g/day + vitamin D supplement, and the mean duration of therapy with alendronate was 24.7 weeks. Patients that used alendronate had a significant improvement in pain as early as 12 weeks, with a reduction in the need for analgesics and improvement in functional capacity in all patients, and this improvement was maintained for 24 weeks. The observation was extended to a total of 60 patients (100 hips), with an average follow-up of 37 months [17]. Alendronate was used in daily doses of 10 mg or weekly doses of 70 mg; these authors confirmed these findings and further suggested that alendronate would retard the progression of AVN and avoid the early indication of surgery in mid-term follow-up [17].

Another study with short-term follow-up was performed by Chen et al., which included 83 patients with non-traumatic AVN of the femoral head [19] – 33 of the patients were ARCO I and the rest were ARCO II. They were given oral alendronate 70 mg weekly, and evaluated with Harris criteria at baseline and 3 months after treatment. In the patients with ARCO I AVN, the scores of pain and function were improved after treatment (P<0.01). Similarly, in the patients with ARCO II AVN the scores of pain and function were both improved after treatment (p<0.01). And the score of activity was also enhanced obviously, which was not observed in ARCO I AVN patients. They concluded that alendronate is effective in treatment of early-stage adult non-traumatic AVN of the femoral head, especially for ARCO II patients.

The first RCT with short-term results evaluating the treatment of alendronate on AVN of the femoral head was by Lai et al. [16]. They studied 40 patients with Steinberg Stage II or III C non-traumatic AVN of the femoral head. The patients were divided into 2 groups, half of them received alendronate 70 mg/week orally and the other half did not receive this medication. The patients were monitored radiologically every 10 weeks and observed for a minimum of 24 months. At the end of the study, the mean HHS was 49.2±9.2 points in the control group and 74.4±7.8 points in the alendronate group. It was also demonstrated that only 2/29 femoral heads with AN (0/17 in Stage II, 2/12 in Stage III) collapsed in the group that received alendronate 70 mg/week, whereas in the group that was randomized to not receive this medication, collapse occurred in 19/25 (9/13 in Stage II, 10/12 in Stage III) femoral heads (p<0.001). One hip in the alendronate group underwent THA, whereas 16 hips in the control group underwent THA (p<0.001). Thus, they concluded that alendronate appeared to prevent early collapse of the femoral head in the hips with Steinberg Stage II or III C non-traumatic AVN.

In a study by Nishii et al. [15], 14 patients (20 hips) with ARCO I–III AVN received alendronate 5 mg/day and were compared in a nonrandomized manner with a group of 8 patients (13 hips) that did not receive alendronate. No patient used walking assistance such as crutches or canes during the study. All the patients received periodical radiologic evaluation at 3, 6, and 12 months. At the end of follow-up, the group of patients receiving alendronate had less pain and a lower frequency of femoral head collapse when compared with the control group. Specifically, they found progressive collapse occurred only in hips with extensive necrosis (greater than the medial 2/3 of the weight-bearing area of the femoral head with/without involvement of acetabula edge, termed Type C2 and C1, respectively) in both groups, which had a much higher incidence in the control groups. In total, collapse occurred in 6/13 of articulations in the control group and in only 1/20 in the alendronate group (p=0.008). Moreover, 2 of 13 hips in the control group needed THA, but none of patients needed surgery in the alendronate group. Therefore they suggested alendronate had the potential to prevent collapse of the femoral head, even with extensive necrosis, within 1 year.

Chen et al. recently performed a 2-year, multicenter, prospective, randomized, double-blind study involving a total of 52 patients (65 hips) [12]. All patients presented with Steinberg Stage IIC or Stage IIIC osteonecrosis. Twenty-six patients (32 hips) were assigned to a scheme of alendronate 70 mg/week for 104 weeks and were compared with a group of 26 patients (33 hips) that received placebo. At the end of the study, MRI evaluation revealed that 21 of the 32 hips in the alendronate group and 20 of the 33 hips in the placebo group had progressed (P=0.636). Four of 32 hips in the alendronate treatment group underwent THA, and 5 of 33 hips in the placebo group had THA (P=0.837). No differences were noted in HHS, or Short Form 36 scores between the 2 groups. Thus, the extensive lesion of necrotic area might impair the prognosis of the AVN when alendronate was used.

LONG-TERM OUTCOMES ANALYSIS:

The long-term data was from a study by Agarwala et al., who presented a clinic radiological analysis of 395 hips with a mean follow-up of 4 years [14] and then further extended the follow-up of 40 patients (53 hips) with AVN to 10 years [13]; those patients were treated with oral alendronate for 3 years, and the data demonstrated although clinical functions showed a general trend of worsening after discontinuation, patients tolerated the decline well, as suggested by the reduction in pain of Ficat and Arlet Stage I–III patients 10 years after onset of alendronate treatment. More importantly, the rates of radiologic progression and femoral head collapse were markedly reduced even at 10 years as compared to the historical data available for natural history of hips with untreated AVN. At 10 years, 46 (87%) of the 53 hips survived, that is, had a satisfactory clinical result. Hip loss to arthroplasty occurred in 1 each of Stage I (7%) and Stage II (5%) hips and in 5 (26%) of Stage III hips. Of the 34 hips that were in pre-collapse stages at the onset of the study, at 10 years 10 had collapsed, indicating a collapse rate of 29% for a period of 10 years. Mean time to collapse was 4.2 years. They thereafter indicated that the benefit is particularly marked if the treatment is begun in the pre-collapse stages of the disease (Stage I or II). Even in Stage III hips some benefit was obtained from treatment with alendronate by at least a delay in the need for total hip replacement [13].

ADVERSE EVENTS ANALYSIS:

None of the studies noted serious adverse effects related to alendronate administration. The most common adverse effects across the studies were gastric dyspepsia mentioned in 3 studies [14,15,19] and dizziness mentioned in 2 studies [13,14], both of which occurred after treatment initiation and were self-limiting. No osteonecrosis of the jaw were seen irrespective of the dose or duration of alendronate.

Many surgical procedures have been described for preventing femoral collapse and progression of AVN. The most studied is core decompression, which works by reduction of intramedullary pressure inside the femoral head by making a drill hole, thus improving blood flow to bone. This procedure is mainly indicated in early-stage AVN [22]. Osteotomy could relocate the necrotic area of bone from the weight-loading area of the acetabulum, so as to redistribute the weight loading to articular cartilage, which is supported by healthy bone [23]. The increasingly applied method is bone graft, aiming to provide mechanical support to subchondral bone or cartilage. There are various types of bone grafting, some combined with osteotomy, osteochondral grafts, muscle pedicle bone grafts, and some are vascularized grafts to improve blood flow of the bone by achieving revascularization [24,25]. The new tantalum rod is made of a biocompatible material with 75% porosity. It has been used to replace the necrotic bone segment to prevent collapse in Steinberg Stage I–III femoral AVN. The presence of pores allows rapid bony ingrowth [26]. However, the efficacy and safety of the above procedures are still controversial [7,27–29]. Due to the reported efficacy of total hip arthroplasty and the typical age of patients with osteonecrosis, it has recently been questioned whether these invasive procedures are appropriate, given the potential difficulty of later conversion to a hip replacement [7,30].

Conservative treatment that helps improve function and delays femoral head deformity could be valuable time-buying strategy for some patients. Some of the pharmacologic agents that have been used to treat osteonecrosis of the hip are statins [31,32], anticoagulants [33,34], prostacyclin [35,36], and Bps [10–19]. The theoretical benefit of statins is based on the association of increased fat cell size with an increased risk of development of hip osteonecrosis [37,38]. Anticoagulants may inhibit the aggregation of platelets and enhance blood flow to ischemic areas of bone [34]. Prostacyclin may promote bone regeneration on a cellular or systemic level [35].

However, collapse of the femoral head appears to be a consequence of the non-coupling of bone reabsorption and bone regeneration rates. In this context, collapse could be prevented if the reabsorptive activity of the necrotic bone during the repair phase was inhibited or slowed until the formation of sufficient new bone [10]. This is the characteristic rationale for use of alendronate in AVN.

The efficacy of alendronate therapy of femoral head deformity was indicated by several experimental studies consisting of both adult rat and rabbit models induced by femoral head ischemia. In 2 closely related studies, alendronate given subcutaneously (200 mg/kg/d) was able to preserve femoral head structure in mature rats during a 6-week follow-up [39,40]. In another study [41], 3-week alendronate therapy reduced degeneration of articular cartilage and improved subchondral bone volume and mineral density in adult rabbits at 12 months, which therefore might be the reason that alendronate treatment could preserve the shape of the femoral head affected by AVN.

Regarding alendronate for the treatment of AVN in clinical trials, in the present review, only 8 articles were published. Our literature search found were 2 recent systematic reviews evaluating BPs for AVN, 1 of which only included 3 observational short-term studies in juveniles [10], and the other with 6 small short-term trials that reported substantial heterogeneities across studies in patient group (adults and adolescents) and treatments (other BPs and combined therapy) [11].

In contrast to previous reviews, the inclusion criteria of the current review were restricted to articles that studied alendronate treatment for adult AVN. We only analyzed alendronate because it was the most widely studied BPs for AVN. Due to ongoing debate on long-term effects of alendronate on the growing skeleton, we limited the studied population to only adults. The inclusion of most recent longer-term results and RCT would also help to update the previous evidence. Furthermore, after determining an overall profile of clinic outcome and the rates of radiographic and clinical failure, the collected data were further stratified by radiographic stage and by duration of follow-up to determine whether any of these factors influenced the results.

However, generally speaking, the studies included in the current review still present various limitations – most used observational non-controlled methods; small numbers of patients; different AVN stages of patients when treatment was initiated; and lack of uniformity in dose and time of alendronate use. These articles, in addition, had various durations of follow-up and were composed of various subgroups of patient populations [13,14].

Bearing in mind the above-mentioned limitations, most studies suggested a positive short-term and middle-term efficacy in pain reduction, improvement of articular function, slowing of bone collapse progression, and delaying the need for arthroplasty in adult AVN patients with the use of alendronate treatment. This is of great clinical significance, as most of the included patients are young or active patients who are likely to require a revision at some point in the future and the effective slowing of femoral head deformity by alendronate could help to avoid early THA. Favorable long-term results were also presented by Agarwala’s 10-year study in treated patients even after alendronate discontinuation [13]. In addition, there were no severe adverse effects associated with alendronate treatment observed during short- or long-term follow-up. Another finding of the current review is that although patients in all stages appeared to have potential benefit from alendronate treatment, the application in early AVN with small size lesion was suggested by most of the included studies. Specially, as shown in Chen’s study, when extensive osteonecrosis (Stage II C and III C) were radiographically presented, alendronate did not have any benefits. Thus, the efficacy of alendronate for AVN with large necrotic legions should be considered more carefully [12].

Conclusions

Our findings support consideration of alendronate use for AVN in adults because short-term and long-term favorable results could be expected, particularly with the early stage and with small necrotic size. Nevertheless, the lack of large-scale, randomized, and double-blind studies should be noted, and future studies should be developed to demonstrate the following aspects. 1) The detailed indication of AVN for alendronate treatment should be further clarified; for example, what type of AVN, traumatic or non-traumatic, which stage of AVN, including what size and what location of the necrotic lesion should be preferentially indicated. 2) There are a number of patient-specific factors that must be considered, including age, comorbidities, life expectancy, health, and activity level. 3) We also need to optimize the strategy of treatment, including timing of treatment initiation and alendronate therapy dose and duration.