AFFs are insufficiency fractures in stress fractures and typically characterized by prodromal symptoms[8], i.e., symptoms of pain, discomfort, weakness in the groin area or on the thigh during weight bearing in the weeks or months prior to the fracture[1, 6, 2]. In this study, 9 (9/16) patients had prodromal symptoms, mainly manifesting as pain, weakness during movement or inability to stand on one leg, and fracture(s) were discovered after seeing a doctor. AFF occurred with minor or no trauma; for case ⑯, the fracture occurred when turning over in bed.
On X-ray, the simple transverse fracture line was revealed. When the fracture line extends to the medial femur, it may become inclined. Complete AFF passes through two layers of cortex, potentially with small tips on the medial side. For incomplete AFF, local periosteal reactions or periosteal thickening of the lateral femoral cortex is often observed[4, 9–11]. In this study, 14 completely AFFs and 10 incompletely AFFs were involved.
Studies have shown that bilateral femoral fractures occur in 40% of AFF patients but in only 2% of patients with common fractures, and another 21% of AFF patients present with focal cortical thickening of the contralateral femur[5, 12, 13]. Eight patients (8/16) in this study had bilateral AFFs; therefore, bilateral femoral X-rays, MRI or bone scans are recommended in unilateral AFF patients.
I. BPs and AFF
BPs mainly inhibit the function of osteoclasts. The long-term administration of BPs excessively inhibits bone turnover, increases bone mineral content, decreases the toughness and energy absorption capacity of bone tissue[16, 17], increases bone fragility, and decreases fracture resistance; therefore, fractures may occur even after no or minor trauma, resulting in transverse fractures[18]. In this study, there were three patients with a history of BP use for more than 10 years. The lowest T values for their hip BMD were − 0.5SD, -0.6SD and − 0.9SD, and AFF occurred when falling from a standing position. Another three patients had a history of Fosamax use for six months, four years and five years. They had no definite history of trauma and only showed anterolateral pain in the thigh. AFF was found during examinations.
When bone turnover is severely inhibited, the mechanisms involved in fracture union may be dysfunctional, leading to delayed union[14]. Bone turnover markers, iliac crest biopsy and fracture site biopsy have confirmed that bone remodeling is inhibited in typical BP-related AFFs[1, 5, 15]. After fracture occurs, osteoclasts cannot participate in bone remodeling, and delay fracture union. In this study, the patient in case ④ took oral Fosamax for four years and continued to take it after surgical treatment of AFF on the left side, and there was no sign of fracture union last 11 months after surgery. When Fosamax was stopped, teriparatide was administered for three months, and the fracture healed.
For patients with a long-term history of BPs using, when injures are caused by slight violence, the fracture site often involves the subtrochanteric femur (6/10), considered a violence action point; when patients report chronic pain, fractures often involve the femoral isthmus (4/10), related to femur anatomical morphology.
BPs can reduce the risk of hip, spine and other fractures by 50–70% and are the main drugs for treating osteoporosis[19, 20]. However, in patients receiving BPs, the exposure time is directly related to AFF risk[5, 21, 22], and the long-term use of BPs (more than five years) has been listed as an independent risk factor for AFF[23]. Multinational guidelines recommend that after oral BPs for five years and intravenous BPs for three years, drug holidays can be considered[24–26, 27]. Our recommendation is regularly monitoring bone metabolism markers and conducting femoral MRI or bone scans during BPs treatment, allowing for the early detection and treatment of incomplete AFF[28].
II. Severe osteoporosis and AFF
Neviaser AS and Hyodo K reported AFFs, that unrelated to BPs[4, 29]. Lim[30] et al. studied 6644 hip fractures and found that the incidence of AFF was 2.95%, of which 24.5% did not involve a history of BPs administration. Kim[31] studied 147 patients with AFF and found that 22% of the patients had no history of BPs using. They both found that severe osteoporosis is an independent risk factor for AFFs.
The lowest T value for hip BMD in this group of patients with severe osteoporosis was − 3.98SD, and three patients had primary osteoporosis. Among the two patients with primary and secondary osteoporosis, one patient received oral glucocorticoids for seven years to treat rheumatoid. X-ray examination revealed subtrochanteric localized periosteal thickening of the left femur due to anterolateral pain in the thigh. After conservative treatment for three months, incomplete AFF was found. Localized periosteal thickening, i.e., “beaking” or “flaring”, is one of the characteristics of AFFs, often appearing one year before the onset of AFFs[32, 33]. Therefore, the presence of “beaking” or “flaring” is indicative of the early stage of AFFs. For the combined administration of glucocorticoids and BPs, 8–10% of patients with periosteal thickening may develop AFF within two years, thus indicating that “beaking” or “flaring” is an important predictor of AFFs[32–35]. Therefore, for patients with severe osteoporosis who receive glucocorticoids long term for other disease, regular imaging examinations of the femur should be carried out to detect the occurrence of “beaking” or “flaring”, especially for those who use BPs concurrently.
Another patient with primary and secondary severe osteoporosis was treated long term with Exemestane after breast cancer surgery. This drug inhibits the conversion of androgen to estrogen, and a side effect is severe osteoporosis. For AFF patients with severe osteoporosis, when a low-energy injury occurs, the fracture site is located in the femoral isthmus, which may be related to the lateral force on the femur when falling; when there is no obvious history of trauma, the fracture site is located in the subtrochanteric region of the femur. We speculate that the stress in the subtrochanteric region of the femur is concentrated and that long-term repeated stimulation eventually leads to fracture, similar to the characteristics of stress fractures.
III. Hip joint dysfunction and AFF
In this study, the AFFs in two patients were caused by hip joint dysfunction. The fracture site was in the subtrochanteric region of the femur. One patient had severe hip OA with limited motion, and the other patient had a thoracic spinal cord injury, leading to a duck-like gait when walking. Abnormal hip function, which affects the stress distribution in the proximal femur, and severe osteoporosis may have been the causes of AFF. At present, there is no literature report on AFF caused by hip joint dysfunction, and more clinical cases are needed for analysis.
IV. Structural abnormality of the femur and AFF
This study found that when abnormal femoral structure (coxa vara or abnormal the lateral FBA) is combined with severe osteoporosis, AFF can occur. David P Taormina reported that there is an obvious relationship between the cervical shaft angle and the development of AFF[36]. Using a computed tomography (CT)-based nonlinear finite element analysis model, Oh Y et al. showed that with a decrease in the cervical shaft angle, the tensile stress in the lateral cortex of the subtrochanteric region increased, eventually resulting in AFF[37]. The patient in case ⑮ had AFF in the subtrochanteric region of the left femur nine years prior, and intramedullary fixation was performed. After surgery, dynamization was performed due to nonunion of the fracture, and the Intramedullary nail was removed until the fracture was completely healed. After surgery, the left cervical shaft angle was 118.1°. The patient was admitted to our hospital due to pain in the right thigh. The lowest T value for hip BMD was − 2.7SD, and the right cervical shaft angle was 103.7°. X-ray revealed a right subtrochanteric incomplete AFF. A new type of interlocking intramedullary nail was used, and the fracture healed three months after surgery.
Many studies report that AFF is a stress fracture related to tension failure of the lateral femoral cortex caused by biomechanical effects over time[5, 38, 39]. Yoo H et al. measured the femurs of 56 individuals and suggested that the lateral FBA threshold should be 5.25° based on the receiver operating characteristic (ROC) curve. In other words, if the lateral FBA is greater than 5.25°, femoral shaft fracture is more likely to occur[40]. The case ⑯ in this group, underwent bilateral total knee arthroplasty, the lateral FBAs of the left and right lateral femurs were 34.7° and 38°, respectively. Anterolateral pain in both thighs occurred during walking one year prior, and X-ray revealed bilateral periosteal thickening of the lateral cortex at the femoral isthmus. Three days before admission, severe pain in the middle and upper part of the left thigh, with limited motion, occurred when turning over in bed, and X-ray revealed a completely AFF at the left subtrochanteric and an incomplete AFF at the right femoral isthmus. A possible mechanism is as follows: when the lateral FBA increases, the tensile force on the lateral cortex and the compressive stress on the medial cortex increases accordingly. Daily loads first lead to the destruction and opening of the lateral cortex, subsequently leading to a complete fracture.
If osteoporosis evaluations and treatment are provided to such patients, it is recommended to perform imaging evaluations and measured the lateral FBA and the cervical shaft angle on the bilateral femur. If the lateral FBA increases or the cervical shaft angle is too small, drug administration is recommended to promote bone formation. If drugs that inhibit bone resorption (such as BPs or denosumab) are selected, the patients should be followed up regularly, and bone metabolic markers should be examined. In particular, if prodromal symptoms occur, femoral imaging examinations should be performed promptly, including X-ray, femoral MRI or bone scans.