Bisphosphonates (BPs) have become the principal treatment for managing osteoporosis during the last two decades. BPs increase bone mineral density (BMD) and prevent fragility fractures [1-3]. However, atypical fractures, particularly of the femur, have emerged as an important concern, suggesting that alternative agents are needed to manage osteoporosis. Long-term use of BPs carries a potential risk for severe suppression of bone turnover, which paradoxically weakens the ability of bone to undergo remodeling. This eventually leads to an accumulation of microdamage, reduced bone toughness, and increased brittleness [4]. Lesions associated with atypical femoral fractures (AFFs) are usually in the subtrochanteric area, and most fractures occur after various prodromal symptoms, such as pain or discomfort around the hip.

Very few BP-associated ulnar fractures were reported in the literature until 2010 [5-13]; however, studies about the treatment and risk factors have been published recently [14-17]. Due to knowledge about this specific fracture, neglect or misdiagnosis of atypical forearm fractures associated with long-term usage of BPs is expected to decrease gradually. Screening inspections of the entire skeleton of patients under long-term BP use include scintigraphy or computed tomography/magnetic resonance imaging, and simple radiography, and these have revealed new information about how BPs affect the entire body. Since 2010, very early lesions in patients under long-term BP use have been detected on simple radiographs by radiologists, and these lesions are now regarded as prodromal lesions that occur before incomplete AFF [18,19].

Interestingly, other specific sclerotic lines (zebra line or pamidronate line) are well known in the pediatric population treated with regular BPs administered for osteogenesis imperfecta, fibrous dysplasia of bone, steroid-induced osteoporosis, or Gaucher disease [20-23]. These lines have been regarded as non-pathological and are a physiological phenomenon associated with a functioning physeal plate.

We also observed the presence of sclerotic lines in the metaphysis of the forearm and lower extremities in patients with AFF following prolonged BP use. In particular, we hypothesized that the sclerotic line identified in the radial tuberosity of AFF patients could be associated with long-term BP therapy. So, we investigate a retrospective case-control study to identify relevant factors.

BPs were stopped in all patients after the AFF diagnosis, even in those with incomplete fractures. Of the 21 patients in group 1, five had atypical forearm fractures, including incomplete lesions, with no significant difference from the proportion in group 2 (seven out of 35, p=0.748). All forearm fractures, including incomplete fractures, occurred later than the AFFs in both groups. The basic demographic characteristics, such as age, sex, smoking, comorbidities of diabetes mellitus or any connective tissue disease requiring steroid treatment, BMD, and the total period of BP administration were not significantly different between the groups (p>0.05) (Table 1).

Multivariate analyses of the variables that were significantly different between the groups were conducted: the time from final administration of BP after the diagnosis of AFF (OR, 47.749; 95% CI, 2.729–835.474; p=0.008) and the concurrent presence of similar lines in the femur (OR, 0.400, 95% CI; 0.196–0.814; p=0.012). Univariate analyses demonstrated that the time from final administration of the BP after the diagnosis of AFF (OR, 0.441; 95% CI, 0.277–0.701; p<0.001) and the concurrent presence of similar lines in the femur were significantly associated with the presence of a sclerotic line in the proximal radius (OR, 36.00; 95% CI, 7.671–168.943; p<0.001). The receiver operating characteristic curve revealed that a cutoff time from final BP administration after AFF diagnosis of 16.5 months predicted a lesion around the radial tuberosity (area under the curve, 0.954 ((95% CI, 0.907–1.000)), p<0.001) (Fig. 2).

The action of BPs involves inhibition of the mevalonate enzyme pathway in osteoclasts and binding to hydroxyapatite crystals in bone. BPs exert direct effects by decreasing the recruitment and suppressing the function of osteoclasts and an indirect effect by provoking osteoblasts to produce an inhibitor of osteoclast formation [21]. Thus, BPs suppress osteoclast-mediated bone resorption, increase BMD, and prevent osteoporotic fragility fractures in the elderly with osteoporosis, but they are relatively rare in pediatric patients with specific diseases.

Sclerotic lines associated with BP are known as “pamidronate lines” or “zebra lines.” These lines are unique to the pediatric population, reflect a temporary slowdown or cessation of rapid longitudinal bone formation in the primary spongiosa, and are parallel to the contours of the contiguous physis [25]. It is now known that these sclerotic lines do not represent “frozen” bars of the growth plate cartilage but rather horizontal trabeculae undergoing turnover [26]. They represent increased bone mineralization because of an indirect response to inhibited osteoclastic activity, rather than a growth arrest phenomenon at the time of drug treatment. Several studies have revealed that growth is not affected by BP usage by showing the radiological features in the metaphysis of the lower extremities of children [27-29]. One interesting point is that the lines gradually disappear 4 years after terminating the BP treatment. Silverman et al. [30] reported that growth plate calcification (zebra line) can be detected on radiographs 3 months after BP treatment. The lesion began to resolve 5 months after discontinuing treatment.

The effect of regular BP use on bony metabolism at the cellular level has been confirmed in pediatric patients such as those with osteogenesis imperfecta. The physiology of the skeleton around the physis, where all cells composing the skeleton play their roles, is extremely active; thus, the influence of an extrinsic agent is fully manifested and well reflected on a simple radiograph. We hypothesized that sclerotic lines similar to those observed around the physis in pediatric patients might also be identifiable in the bones of elderly patients undergoing long-term BP therapy for osteoporosis, particularly in areas where bony metabolism is more active due to external forces or other factors. In fact, we identified similar lines at the metaphysis of the distal femur or proximal tibia and around radial tuberosity in some cases (Figs. 1, 3). However, these old-age lines were not parallel, which was likely a result of variations in administration of the agent, such as dosage and the related cycle in patients with osteoporosis.

Although sclerotic lines around the radial tuberosity could be regarded as less clinically relevant, there are three reasons why they are related to BP use. First, sclerotic lines around the radial tuberosity were found in group 1 patients, who had previous AFFs or AFFs with atypical forearm fractures, and who were undergoing long-term BP therapy. Second, in one of group 1, both an atypical ulnar fracture and a proximal radius fracture were observed (Fig. 4). Given that the fracture site was not typical by trauma and the fracture pattern was transverse with minimal comminution, it is also considered an atypical fracture. Finally, the typical location of atypical fractures associated with BP therapy is an area under tensile force, rather than the skeleton under compressive force. Although the proximal radius is an extremely rare site considering previous studies, it is believed that the supinator muscle, which attaches to the radial tuberosity, may have subjected it under tensile stress. If there is no suspicion of an atypical fracture, many orthopedic or traumatic surgeons have attempted open reduction and internal fixation with the understanding that it was an ordinary fracture originating from a Monteggia injury-like mechanism.

Given that atypical fractures can occur at the radial tuberosity, the observed sclerotic line at this site may be considered a consequence of both the external forces exerted on the bone and the use of BPs. Additionally, since these sclerotic lines were observed at the time of diagnosis of AFF or AFF with an atypical ulnar fracture, it suggests that the sclerotic lines were present before the occurrence of atypical fractures due to BP use. This implies a significant alteration in bone physiology caused by BP.

Based on the results, considering the timing of the AFF diagnosis and the duration of BP use, the presence of a sclerotic line at the radial tuberosity suggests that BP treatment was likely ongoing up until relatively recently. The receiver operating characteristic analysis further suggests that the sclerotic line is most likely to be observed approximately 16.5 months after the last BP use. Based on the observation that a majority of patients (17 out of 21) with a sclerotic line at the radial tuberosity also presented with sclerotic lines in the lower extremities, it is important to consider that a proximal radius fracture with an atypical pattern, particularly if accompanied by sclerotic lines in the lower extremities, may not be due to typical trauma but rather an atypical fracture induced by BP therapy.

Some limitations of the current study should be discussed. First, The subjects of this study were patients diagnosed with AFF who underwent forearm X-rays. This selection criterion may introduce bias in the patient cohort. Since 2017, our institution has taken an interest in atypical ulnar fractures resembling AFF, leading to forearm X-rays in the majority of patients diagnosed with AFF. However, In a very small number of patients, the X-rays were taken incidentally during the diagnosis of other diseases such as epicondylitis, traumatic arthritis, and De Quervain disease between 2010 and 2017. Also, if an X-ray was taken in cases of symptoms like forearm pain or even incomplete fractures, it could introduce bias into the statistics. However, since most patients in the study were those who had X-rays taken for screening purposes after 2017, the sample remains meaningful.

Second, we were unable to determine whether the lines themselves were associated with the fracture line of an atypical fracture. Most AFFs are distinct from sclerotic lines, and many AFFs do not reveal these lines concurrently. In a few patients, the lines abruptly disappeared during reaming for intramedullary fixation using interlocking nails (Fig. 5). Also, the endosteal reaction was reported as a very early finding of BPs by Mohan et al. [18]. Thus, we presumed that the lines would be located in the medulla or endosteum of the metaphysis, rather than the cortex. Third, because this study was not a prospective comparative trial, precise information about the lines associated with several kinds of agents, the time of administration, and the drug holiday was not fully understood. A pathological study based on molecular analyses should be performed to obtain more information. A micro-computed tomography study to examine the micro-architecture of the bony trabeculae or cortical geometry influenced by BPs would be helpful.

Conclusively, some AFF patients had sclerotic lines on the proximal radius. These lines were particularly more frequent in patients who had been treated with a BP until recently, and almost identical lines were observed in the lower extremities.

For patients with a history of long-term BP use, it is recommended to perform regular hip X-rays as part of AFF screening, as well as forearm and knee X-rays. If sclerotic lines are detected, it is important to inform the patient about the potential risk of atypical fractures and consider adjusting osteoporosis medication. However, more studies are needed to determine whether these lines are a precursor to an atypical fracture.