Atypical metatarsal fracture in a patient on long term bisphosphonate therapy.

A 24 years old female of cushing disease had undergone adrenelectomy. She was put on alendronate and steroid. After six and a half years she developed pathological fracture subtrochanteric femur. The patient was treated with proximal femoral nailing and the fracture united. 2 years later she developed pain right foot. She was diagnosed as transverse fracture of fifth metatarsal. We report this rare case of atypical metatarsal fracture in a patient on long term bisphosphonate therapy.

INTRODUCTION

Bisphosphonates are the preferred drugs in postmenopausal and corticosteroid-induced osteoporosis.1–5 Long term therapy with bisphosphonates results in significant rise in bone mineral density (BMD) of spine and hip.6–8 Subtrochanteric and femoral shaft fractures may occur in patients who have been treated with long term Bisphosphonates, but are limited reports regarding pathological fractures at other musculoskeletal sites.69–12 We report a rare case report of alendronate-induced pathological metatarsal fracture.

CASE REPORT

A 24-year-old female with diagnosis of Cushing's disease (ectopic ACTH syndrome) had undergone adrenalectomy in 2000. She was kept on low-dose steroids postoperatively. The patient started having pain in the left hip 2 years postadrenalectomy, for which she was given analgesics and calcium supplementation. Her BMD (T score: –3.3; lumbar spine and –2.6; proximal femur) and radiological examination suggested severe osteoporosis. She subsequently suffered pathological fracture neck of femur for which she was operated and valgus osteotomy was done. Postoperatively, she was advised alendronate 70 mg once a week with calcium supplementation along with low-dose steroid for post adrenalectomy supplementation. After 6 years, the patient again started having pain in the right hip and thigh. Her BMD was found to be improving (T score –1.1) and there was no radiological evidence of osteoporosis as well. She was advised analgesics, exercises, along with the previous treatment, but her pain did not subside. After 5 months, she had aggravation of pain and on radiological evaluation was found to be having pathological subtrochanteric fracture for which she was operated and internal fixation with long proximal femoral nail was done [Figure 1a]. The fracture united at 10 months and pain in thigh and hip subsided [Figure 1b]. The patient continued to take alendronate along with low-dose steroid for post adrenalectomy supplementation. Two years later the patient started having diffuse dull ache, insidious in onset, activity related pain in the right foot which did not subside completely with analgesics and physical therapy for 3 months. The radiographic evaluation showed incomplete, transverse, diaphyseal fracture of fifth metatarsal shaft with thickening of lateral cortex [Figure 2a]. Patient's BMD showed normal mineral density (T score –0.7). She was advised plaster. Alendronate therapy was discontinued and teriparatide therapy 20 mcg subcutaneously was started and continued for 6 months. She improved and the fracture healed, and after 5 months, she was able to walk without walking aid and was doing all her household activities [Figure 2b].

Figure 1

(a) X-ray both hip joints with proximal half of femur (anteroposterior view) showing bisphosphonate induced pathological subtrochanteric fracture right hip in postadrenalectomy patient on long term bisphosphonate therapy. The X-ray also shows a healed fracture neck of femur treated by valgus osteotomy. (b) Ten-month followup anteroposterior radiograph showing union after internal fixation with proximal femoral nail

Figure 2

(a) Radiograph of right foot (anteroposterior view) showing alendronate induced atypical fracture of fifth metatarsal which is transverse, incomplete, diaphyseal fracture with characteristic thickening of lateral cortex (b) radiograph at 5 month followup showing fracture union

DISCUSSION

Bisphosphonates are the most widely studied and used first-line drugs in postmenopausal and corticosteroid-induced osteoporosis.3–51314 Alendronate, risedronate, and ibandronate are currently approved by FDA for use in osteoporosis.15 Bisphosphonates bind avidly to mineralized bone surfaces and reduce osteoclastic bone resorption and result in increased mineral density in the dual energy X-ray absorptiometry [DEXA] scan.12 Paradoxically, this dense bone is weaker, brittle, and prone to pathological fracture. Alendronate significantly increases bone density of spine and hip and reduces the incidence of osteoporotic fracture up to 50%.7816 Even when discontinued after 5 years, the physiological effect on bone resorption remains for 5 years thereafter, with no increase in fracture risk.817

Parathormone (PTH) is an anabolic agent that acts by stimulating bone formation. Continuous exposure to high-dose PTH increases osteoclast differentiation which leads to bone resorption. On the contrary, intermittent injections of low-dose PTH produces increase in osteoblast number and function by promoting osteoblastogenesis and decreasing osteoblast apoptosis,18–20 leading to bone formation, thickening of cortices and existing trabeculae of the skeleton, and perhaps increasing trabecular numbers and their connectivity.18 Teriparatide is a recombinant form of human parathyroid hormone approved by the FDA for treatment of osteoporosis in postmenopausal women who are at high risk for fractures.21

This anabolic agent is especially indicated in patients with severe osteoporosis with high risk of fracture. The benefit of PTH persists when antiresorptives are maintained and its use for more than 2 years is not recommended.12 In 2005, Odvina et al. identified a group of nine patients who developed spontaneous non-spinal fractures while on long term alendronate. These non-traumatic fractures involved skeletal areas rich in cortical bone, such as the femoral shaft, pubic bone, and ischium, and were considered atypical for osteoporotic fractures.22 Bone biopsies in all demonstrated severe suppression of bone turnover (SSBT). Goh et al. reported a series of 13 patients with low-energy subtrochanteric fractures in which patients on alendronate had a higher incidence of simple transverse or short oblique fractures (89%) as opposed to the patients with osteoporosis not receiving bisphosphonates (0%).23 Approximately 55–76% of the patients with bisphosphonate-related fractures had prodromal pain prior to fracture completion, whereas none of the patients with fractures solely due to severe osteoporosis in the absence of long term alendronate had prodromal pain.7

It has been reported that the long term use of alendronate,91523–25 especially in those patients who have normal BMD, leads to severe suppression of bone turnover, resulting in bone pain and pathological fracture. In experimental studies, alendronate has been shown to inhibit normal repair of microdamage arising from SSBT, which in turn results in accumulation of microdamage. In addition to microdamage accumulation, chronic oversuppression of bone turnover by alendronate may allow secondary mineralization to continue, resulting in hypermineralized bone which has high Young's modulus of bone elasticity but low work to fragility values (a measure of fracture toughness).26–32

Alendronate associated fractures may be bilateral,923 have unique radiological features like transverse fracture orientation with preexisting ellipsoidal thickening of lateral femoral cortex and medial beak, and are likely to be preceded by prodromal pain and occur with no or trivial trauma. These fractures are particularly reported in subtrochanteric and diaphyseal region of femur, but our case report shows that long term alendronate therapy may result in concomitant pathological fracture at other musculoskeletal sites as well.

In our case a postadrenalectomy patient with limited functional activities and history of two fractures in the past, was on long term alendronate therapy for 8 years, and was having normal bone stock with near-normal BMD (T score –0.7). This patient had fracture of fifth metatarsal with features like prodromal symptoms preceding the fracture without any history of trauma and characteristic features like incomplete, transverse diaphyseal fracture with thickening of lateral cortex at fifth metatarsal.

These fractures are difficult to unite with conservative management.23–25 Current accepted guidelines for treatment of incomplete or complete fracture is surgical treatment along with withdrawal of bisphosphonate therapy and introduction of low-dose teriparatide 20 mcg daily subcutaneously for 3–6 months. There is marked improvement in BMD after long term use of alendronate, but this prolonged treatment does not appear safe as this may result in SSBT in some patients.23–25

Alendronate was used in our case after the onset of steroid-induced osteoporosis. After long term use of this drug, the patient started having prodromal symptoms like thigh pain and then atraumatic subtrochanteric fracture and atypical metatarsal fracture thereafter, creating a doubt on the safety of long term use of alendronate even in well-indicated patients. It would have been reasonable to stop the drug when our patient had atypical subtrochanteric fracture of the right femoral shaft.

Bisphosphonates are useful for the treatment of osteoporosis, but there are safety concerns about long term use of alendronate, which may lead to SSBT and unusual fractures. The patient in this case report took long term alendronate therapy for 8 years and sustained two non-traumatic alendronate-induced atypical fractures. If we had discontinued alendronate and started teriparatide at the time of atypical subtrochanteric fracture management, unusual metatarsal fracture which is rare would not have evolved. We advise clinicians should screen the patients on long term alendronate therapy for prodromal symptoms and consider the use of radiographs to detect the insufficiency stress fracture. In situations where characteristic atypical fractures have already developed, one should strongly consider discontinuing this drug.