Strontium ranelate in fracture healing and joint pain improvement in a rheumatoid arthritis patient

Summary

Rheumatoid arthritis is a chronic inflammatory disease characterized by cartilage and bone destruction leading to functional disability. Patients with rheumatoid arthritis also are inclined to have lower bone density and to develop osteoporosis, a condition that leaves them more prone to fractures. With improper care, these incapacitated patients can develop increased morbidity and mortality. Strontium ranelate, currently prescribed for osteoporosis, can be especially helpful in rheumatoid arthritis by strengthening bone quality, reducing fracture risks, and promoting fracture healing. We report a 62-year-old woman with rheumatoid arthritis who suffered a periprosthetic fracture of the femur. After five months of treatment with systemic administration of strontium ranelate, she achieved pain-free ambulation and near union of the aforementioned fracture. In addition, she reported a significant improvement of her polyarthralgia, so that she could stop taking analgesics for her underlying condition in the second month of strontium ranelate therapy. Given this unexpected result, we propose that besides its already known pharmacological effects, strontium ranelate could have an additional benefit in improving polyarthralgia in rheumatoid arthritis patients.

Introduction

Rheumatoid arthritis (RA) is a complex progressive disease characterized by musculoskeletal manifestations such as chronic synovial inflammation, cartilage destruction, and bone erosion (1). Physiologically, these symptoms have been linked to increased levels of the proinflammatory cytokine interleukin-1 (IL-1), which favors osteoclast differentiation and activation, leading to bone resorption and net bone loss (2). In addition, it stimulates the release of synovial enzymes causing degradation of articular cartilage (3). Consequently, the strength and loading capacity of the joints are vastly diminished, resulting in more destruction and pain (4). Because of these mechanisms, RA involves an elevated risk of reduced bone mineral density (BMD), osteoporosis and therefore fractures (5, 6). Since joint deformities in these patients already cause incapacitation in daily activities, prevention and treatment of fractures must be of utmost importance. Strontium ranelate (SR), an anti-osteoporotic drug which increases bone formation and decreases bone resorption, seems fitting for RA patients as it improves bone microarchitecture, decreases fracture risks, and promotes fracture healing (7–9).

We present the case of a RA patient who suffered a periprosthetic fracture of the femur treated with systemic administration of SR. As a result, she not only achieved marked fracture healing but also coincidentally improved multiple joint pains. Through literature review, we will update the current concepts regarding the role of SR in fracture healing and propose a mechanism on how it can relieve polyarthralgia in a RA patient.

Case report

Patient is a 62-year-old woman who has undergone medical treatment for RA for the past 50 years. Despite early diagnosis and pharmacological therapy, the disease debilitated her life with polyarthralgia involving bilateral hands, wrists, elbows, shoulders, ankles, knees and hips. Over the past 20 years, the progressive joint deformities led to surgery on her right wrist along with total arthroplasties of both knees and both hips. In addition, she required a total knee revision surgery seven years ago after suffering a right distal femur periprosthetic fracture. Despite medical and surgical interventions, multiple joint pains persisted with a subjective score of 6–7 on the Visual Analogue Scale (VAS).

Two years ago, she was involved in a motor vehicle accident when her right leg was trapped under an overturned moped. She presented to the emergency department complaining of severe pain in her right thigh. Physical examination revealed evident swelling, tenderness and limited range of motion in her right leg. No neurovascular abnormalities were detected. Initial radiography revealed a non-displaced periprosthetic fracture near the junction between the upper and middle third of the right femur (Figure 1). Since she already had existing ipsilateral knee and hip prostheses with both ends of the femur occupied, the combined implants effectively served as one intramedullary nail fixating and stabilizing the fracture. In addition, the cement used during total knee revision surgery further strengthened the distal component of the femur. Because the fracture was stable and well fixed, non-operative management was recommended. Patient was prescribed SR (2 g/day), as well as calcium (600 mg/day) and vitamin D (800 UI/day) supplementation, in the hopes of accelerating fracture healing and achieving bony union.

Figure 1.

Radiograph of the right femur showing a non-displaced periprosthetic fracture near the junction of the upper and middle third.

During the two-month follow up, patient stated that her thigh pain was much better as passive movement did not cause any discomfort. Radiograph confirmed callus formation seen at both the medial and lateral cortices (Figure 2). Specifically, advanced callus formation in the former was evident as the fracture rim was barely visible. On radiographic follow-up after five months of treatment, the fracture rims had disappeared and there was evidence of structural bone remodeling at the lateral cortex as well, with near union of the medial cortex (Figure 3). The rapid bone healing correlated well with the clinical finding of pain-free ambulation with the help of a cane. At one and a half year post-SR therapy, patient was asymptomatic and she could move her right leg freely and achieve full range of motion, indicating complete healing of the periprosthetic fracture.

Figure 2.

Radiograph at two months after strontium ranelate therapy showing evident callus formation.

Figure 3.

Radiograph at five months after strontium ranelate therapy with near healing of the fracture.

Along with SR, patient initially continued her treatment of RA with prescribed analgesics as before. But as pain from the fracture gradually subsided, she also found noticeable relief for her polyarthralgia. As she continued the SR therapy and stopped the analgesics after the second month, joint pain improvement continued. In addition, she stated that joint swellings have decreased noticeably after six months of treatment, allowing better range of motion and ambulation. At the one-year follow up, patient had achieved good functional recovery with 0° to 105° of motion in her right knee and the following ranges of motion in her right hip: 107° of flexion, 23° of extension, 40° of internal rotation, 26° of external rotation, 45° of abduction, and 15° of adduction. For the past 18 months, patient has been willing to continue SR therapy because she firmly believes that it is solely responsible for reducing her multiple joint pains. In fact, she now grades the pain between 2 and 3 on the VAS. It seems, therefore, that SR not only promoted fracture healing but also relieved multiple joint pains. Given these results, we propose that SR has an additional beneficial effect when it comes to treating polyarthralgia in a RA patient.

Discussion

The effects of SR in the treatment of osteoporosis and reduction of fracture risks have been well established in extensively-controlled clinical studies (10, 11), with its efficacy lasting up to eight years, independent of individual risk factors (12). With respect to fracture healing, SR accomplishes this task through its ability to strengthen bone quality and microarchitecture (8). As it rebalances bone turnover in favor of bone formation, it promotes endochondral ossification via increasing callus volume, BMD, and biomechanical strength and improving callus microstructural properties (9). Several studies have also shown that SR-treated patients demonstrate higher trabecular number, lower trabecular separation, and higher cortical thickness with positive effects on the overall osteoblast activity and number. In addition, increased bone volume through greater mean cortical thickness indicates that periosteal bone formation can be stimulated by SR (12–15). As evidenced by the results from our patient, SR certainly plays an important role in fracture healing, especially when bone quality is compromised such as in osteoporosis.

Besides fracture healing, recent studies have demonstrated a promising new role for SR in the treatment of osteoarthritis (OA). In a three-year international study, the Strontium ranelate Efficacy in Knee OsteoarthrItis triAl (SEKOIA), treatment with SR produced a reduction in joint space width, symptomatic enhancement through lower pain scores, and overall improvement in knee pain (16). In another experiment performed on dog models, Pelletier et al. (17) demonstrated that SR significantly reduces cartilage erosion and subchondral bone plate thickness. In addition, the synovial membrane showed significant reduction in the gene expression of IL-1 beta (IL-1β), a cytokine from the same family as IL-1 that is prominent in the synovium in both OA and RA. Although the exact mechanism of IL-1β reduction remains unclear, it is precisely through this pathway that SR may exert its joint-pain-reducing effect in a RA patient.

Current treatment strategies for RA have focused on minimizing disability through control of inflammation and protection of bone and cartilage by targeting IL-1. Overall, whether through blockade, deletion, or inhibition, studies have shown its effects on the reduction of joint space narrowing, cartilage damage, and bone loss. Even if patients with active RA discontinue their anti-rheumatic drugs, the beneficial effects are still exhibited along with significant improvement in clinical signs and symptoms such as number of tender joints, average pain score, and duration of morning stiffness (18–20).

From the results in the aforementioned studies and trials, we correlate and propose the following statements. First, SR has proven efficacy in reducing fracture risk and promoting fracture healing. Second, SR improves symptoms and signs of OA by reducing the concentration levels of IL-1. Third, both OA and RA express the same IL-1 family of cytokines, which has been implicated in their pathogeneses. Lastly, reduction of IL-1 provides radiographic and clinical improvement in RA. Therefore, because our patient previously suffered from polyarthralgia, and taking SR alleviated her joint pains, we suggest that SR may achieve its pain-alleviating effects in RA, as in OA, through reducing the concentration levels of IL-1.

Without a doubt, our proposal lacks concrete evidence such as BMD and IL-1/IL-1β concentrations to justify our analysis. In addition, this limited result only comes from the radiographs, clinical presentation, and satisfaction of a single patient. Clearly, such coincidental findings do not warrant recommending routine usage of SR in RA patients for polyarthralgia. More supportive data would be valuable and is obviously needed, such as from a prospective study with a large cohort of RA patients.

Although the symptomatic relief or regression of disease manifestations could not represent a cure for this chronic illness, the proposed and indirect effect of SR on IL-1 with the purpose of reducing joint pain brings new hope. Well-designed studies of longer duration are necessary to establish the real benefits and safety of SR. Nevertheless, the result from our patient not only demonstrates that SR has a valuable role in the treatment of RA and osteoporotic fracture healing, but also hints at a potential role in the treatment of RA-associated polyarthralgia. It is our sincere hope that more case reports like this one will inspire researchers to design studies that convincingly prove this additional effect of SR and, ultimately, benefit patients with RA.