Multiple myeloma is an incurable bone-marrow-based plasma-cell dyscrasia1,2, characterized by increased bone loss3,4. Patients with multiple myeloma commonly have osteolytic bone destruction resulting in hypercalcemia, pathologic fractures, spinal cord compression, and pain5.
The nitrogen-containing bisphosphonates (N-BPs), zoledronic acid and pamidronate, are potent inhibitors of bone loss6,7. When administered intravenously (IV) on an ongoing monthly basis, these drugs reduce the occurrence of skeletal complications in patients with multiple myeloma8-12, and monthly IV N-BP therapy is the current standard of care for these patients. N-BPs are also effective in the treatment of patients with metastatic bone disease and some benign disorders associated with increased bone loss13-15. Preclinical studies have demonstrated that N-BPs exert many antitumor effects16,17. Recent clinical studies have shown that these drugs, especially zoledronic acid, can improve the survival time of patients with cancer18,19. A recent large randomized trial from the Medical Research Council involving previously untreated patients with multiple myeloma demonstrated that monthly administration of zoledronic acid improved overall survival time compared with that of patients treated with daily oral clodronate, a weaker non-N-BP20. Since these results will likely lead to more prolonged zoledronic-acid treatment for multiple myeloma, complications of long-term N-BP therapy will become important to identify.
Bisphosphonate therapy has been paradoxically linked to osseous complications occurring in specific anatomic locations. Osteonecrosis of the jaw in patients being treated with IV N-BPs, which we believe was first documented in 200221, is more frequently observed among patients with multiple myeloma than in patients with other types of metastatic bone disease22,23. Fractures at specific anatomic sites have been linked to five years or more of bisphosphonate therapy. Nine cases of long-bone fractures and one metatarsal fracture were reported after long-term treatment with oral alendronate24,25. The literature suggests a correlation between long-term alendronate use and femoral subtrochanteric stress and pelvic insufficiency fractures26-28, and alendronate has been associated with an increased occurrence of femoral stress fractures without a traumatic cause29,30. Two cases of spontaneous non-spinal stress fractures in patients on long-term IV N-BP therapy for multiple myeloma have been reported31,32, and one of our patients recently developed a femoral fracture. In October 2010, the U.S. Food and Drug Administration issued a warning concerning the use of N-BPs, and a statement denoting the increased risk of subtrochanteric and diaphyseal femoral fractures has been added to N-BP osteoporotic drug labels under the "Warnings and Precautions" section33.
We report on six patients with multiple myeloma who developed metatarsal stress fractures while receiving long-term IV N-BP therapy. The patients were informed that data concerning their cases would be submitted for publication, and they provided consent.
Stress fractures occur as a result of repetitive loading and unloading of bone34,35. Increased strain or frequency of compression and tension loads can lead to microfractures, which are repaired during bone remodeling. If extensive microdamage is sustained before sufficient bone remodeling occurs, a stress fracture can result36,37. These fractures are most often observed in the lower-extremity bones in runners, dancers, and military personnel. However, they are also seen in patients with rheumatoid arthritis, metabolic bone disease, and neuropathies38,39. The metatarsals are common sites of stress fractures40.
Case 1. A fifty-seven-year-old man was diagnosed with International Staging System (ISS)41 stage-I and Durie-Salmon42 stage-I immunoglobulin G (IgG) kappa multiple myeloma in May 1997. (The staging criteria are summarized in Table I.) The patient developed a pathological fracture of the C5 vertebral body. The findings of histologic evaluation of the lesion were consistent with the diagnosis of plasmacytoma. The tumor was resected, and the patient underwent a C4-C6 combined anterior-posterior cervical spine fusion. The serum monoclonal (M)-protein spike was 1.4 g/dL with a serum IgG level of 1580 mg/dL. The bone marrow showed 10% plasma cells, and a skeletal survey revealed lytic lesions in the spine. The patient was started on 90 mg of IV pamidronate monthly. In July 2001, after new lytic lesions were found in the sacrum and ilium, he was started on 50 mg of oral prednisone every other day, and was switched from pamidronate to 4 mg of IV zoledronic acid every three weeks, which he continued to receive on an ongoing basis. The M-protein level remained stable.
In March 2008, the patient developed pain in the left midfoot while on a hike. Radiographs revealed a stress fracture at the base of the second metatarsal. The patient was treated with activity restriction and an orthotic device in his shoe. The symptoms largely resolved over the ensuing twelve weeks, and follow-up radiographs at six months showed complete healing of the fracture. In February 2010, the patient began experiencing renewed symptoms, especially while exercising. Over the next ten months, he sporadically reported pain in the left foot, which he treated inconsistently with a controlled ankle motion (CAM) walker and a bone-growth stimulator. At the time of the last follow-up, his condition had improved, but he continued to experience occasional pain while exercising.
Case 2. A fifty-three-year-old man was diagnosed with ISS stage-I and Durie-Salmon stage-I IgA lambda multiple myeloma in the spring of 2000. His serum IgA level was 1130 mg/dL. A skeletal survey revealed no lytic lesions. He started treatment with 50 mg of oral prednisone every other day and 90 mg of IV pamidronate monthly. Within a year, the patient was switched to monthly zoledronic acid infusions. The therapies for multiple myeloma varied as the disease progressed, and included combinations of bortezomib with melphalan as well as thalidomide or lenalidomide with glucocorticosteroids.
In December 2007, the patient developed intermittent pain in the left foot while walking. Treatment consisted of oral clarithromycin daily and oral Medrol (methylprednisolone) every other day. He had numbness, coldness, and tingling in both feet. On palpation of the left fifth metatarsal, there was point tenderness proximally at its base. Neurologically, the lower extremities demonstrated intact sharp/dull, vibratory, and Semmes-Weinstein monofilament (5.07 mm) sensation. Active-resisted eversion of the foot caused pain. Radiographs revealed a Jones fracture of the base of the left fifth metatarsal with minimal displacement (Fig. 1). He was provided with a CAM walker and crutches, and a bone-growth stimulator was prescribed because of the propensity for nonunion of this fracture43. Four months later he was pain-free, but repeat radiographs showed a delayed union of the fracture. He remained asymptomatic at the time of the last follow-up.
Case 3. A fifty-six-year-old man was diagnosed in June 2000 with ISS stage-I and Durie-Salmon stage-I IgA kappa multiple myeloma. Laboratory findings were remarkable for a serum M-protein level of 3.9 g/dL and a serum IgA level of 4770 mg/dL. A bone survey showed no lytic bone disease. He received 4 mg of IV zoledronic acid monthly. Interestingly, the patient responded to the zoledronic-acid treatment with steady decreases in the serum M-protein level to 1.66 g/dL and the serum IgA level to 2140 mg/dL by August 2006. In January 2004, the patient was diagnosed with osteonecrosis of the jaw in the lingual side of the left mandible. The osteonecrosis completely resolved without specific medical or surgical interventions over the next year. In September 2007, the patient began treatment with oral melphalan and bortezomib because of progression of the myeloma.
In January 2008, the patient noted swelling in the left foot and a sharp, burning pain that was aggravated by walking. He also had experienced a mild peripheral neuropathy with burning and numbness in the toes for several months. Physical examination revealed localized edema and tenderness over the fifth metatarsal. Although radiographic findings appeared normal, magnetic resonance imaging (MRI) revealed an incomplete transverse fracture of the proximal metaphysis of the fifth metatarsal (Fig. 2). Bone mineralization and the surrounding soft tissues appeared normal. The patient was given a CAM walker and instructed to refrain from excessive weight-bearing activity. He used the CAM walker only intermittently and maintained an active lifestyle. He appeared to make an initial recovery but experienced recurrence of pain in the left foot in February 2009. An MRI scan at that time showed a healed fracture of the proximal fifth metatarsal. After several months, during which he refused to use the CAM walker, the pain in the left foot improved and then completely resolved. At the time of the latest follow-up, the patient was able to walk and participate in vigorous hikes without limitations.
Case 4. A fifty-seven-year-old man was diagnosed with ISS stage-I and Durie-Salmon stage-III IgG kappa multiple myeloma in March 2000 following the discovery of lytic lesions in the skull, clivus, ribs, and pelvis. His laboratory workup showed a serum M-protein level of 1.4 g/dL and a serum IgG level of 1900 mg/dL. In addition to receiving 90 mg of IV pamidronate monthly, he was treated with five IV cycles of vincristine, doxorubicin, and dexamethasone followed by 50 mg of oral prednisone therapy every other day.
In 2002, the patient was switched from pamidronate to 4 mg of IV zoledronic acid monthly. In June 2003, he developed progressive disease, and thalidomide was added to his treatment regimen. He then had three rib fractures and discontinued the prednisone therapy. The disease progressed in 2004, and oral methylprednisolone was added in May 2005. In September 2007, the patient showed progressive disease, and oral clarithromycin was added; however, there was no response to this medication. Two months later, the patient developed a fracture of the base of the right fourth metatarsal, which healed slowly with CAM-walker protection and limitation of weight-bearing over the next four months.
Because of progressive disease, the patient started IV bortezomib and oral melphalan therapy in January 2008, and there was a positive response. In April 2008, while receiving this treatment, he experienced pain and swelling in the left foot. The pain was at the base of the fourth metatarsal. Radiographs revealed a persistent but partially healed stress fracture in the right fourth metatarsal and confirmed a new stress fracture at the base of the left fourth metatarsal. Despite these fractures, the patient traveled to the Himalayas and hiked extensively with stiff-soled hiking boots, orthotics, and walking sticks and experienced only minimal pain. On follow-up, mild edema was observed at the base of the fourth metatarsal of the left foot, and there was pain with deep palpation. Radiographs made six months later showed a persistent gap between the fracture elements bilaterally; a small amount of osteoid was notable in the lucent areas, but no frank osseous bridging was appreciated in either fourth metatarsal. With overuse, the patient experienced mild pain and discomfort, which were relieved with a variety of oral nonsteroidal anti-inflammatory drugs. At the time of the latest follow-up, he had slight pain intermittently, especially immediately following the administration of each dose of zoledronic acid.
Case 5. A sixty-five-year-old woman was diagnosed with ISS stage-I and Durie-Salmon stage-I IgA lambda multiple myeloma in April 2002 following the onset of neuropathy with numbness of the lateral aspect of the left calf. The serum IgA level was 2230 mg/dL. A bone marrow biopsy showed 20% to 25% plasma cells, a bone survey showed no lytic lesions, and she had a normal complete blood-cell count. She received no treatment for the multiple myeloma until July 2004, when she received 90 mg of IV pamidronate and another dose three months later, and then continued this treatment monthly. In March 2006, she switched to 4 mg of IV zoledronic acid monthly. In addition, she was treated with a variety of bortezomib-containing regimens without glucocorticosteroids.
In September 2009, the patient reported pain at the base of the fifth metatarsal of the right foot. She was receiving bortezomib and was experiencing mild peripheral neuropathy. Radiographs revealed a nondisplaced incomplete Jones fracture at the base of the fifth metatarsal. She used a bone-growth stimulator and a CAM walker. Follow-up two months later revealed partial healing of the fracture. At the latest follow-up, four months after the fracture, there was no pain at the fracture site and she was asymptomatic.
Case 6. A forty-three-year-old woman was diagnosed with ISS stage-III and Durie-Salmon stage-III IgA kappa multiple myeloma in April 1997. Radiographs were negative for lytic lesions. Her laboratory workup showed a serum IgA level in the range of 5000 mg/dL and a serum β-2M level of 6.2 mg/L. She was treated with 90 mg of IV pamidronate monthly. The patient also received three cycles of vincristine, doxorubicin, and dexamethasone. In August 1997, she was treated with high-dose chemotherapy followed by autologous stem-cell transplantation. Following the transplant, she continued monthly pamidronate therapy and was placed on maintenance therapy with oral dexamethasone. The disease returned in September 2005, at which point daily oral clarithromycin was added. At that time, the patient had no evidence of peripheral neuropathy.
In January 2006, the patient experienced pain and inflammation in the right foot. Radiographs revealed a transverse, nondisplaced, nonacute fracture through the base of the fourth metatarsal. The patient immobilized her foot via taping, which minimized pain, and she had complete resolution of pain by the end of April 2006.
In April 2010, the patient experienced a sudden sharp pain in the same foot while walking, even though she did not recall sustaining any injury. She exhibited some evidence of mild peripheral neuropathy at that time. There was marked tenderness and mild swelling in the region of the fifth metatarsal, and radiographs revealed an acute nondisplaced fracture through the base of the fifth metatarsal. The patient used a CAM walker and a bone-growth stimulator. Three months later, she had improved mobility and much less pain. Over the next several months, the pain completely resolved, and she remained asymptomatic.
The risk of fractures due to long-term bisphosphonate therapy has been reported with increasing frequency25,43-46. Subtrochanteric stress fractures, pelvic insufficiency fractures, and femoral fractures have all been linked to long-term bisphosphonate use21,26,28-30, and one metatarsal stress fracture has been observed25. Until recently, these known adverse effects had occurred solely in osteoporotic patients receiving oral alendronate. A large retrospective study from the Mayo Clinic following patients with multiple myeloma treated largely before the widespread use of zoledronic acid or pamidronate (1945 to 2001) revealed no spontaneous foot or toe fractures47. However, in 2008 and 2009, two separate cases of spontaneous femoral fracture in patients with multiple myeloma with nine and eleven-year histories of IV bisphosphonate therapy were reported31,32, and we recently observed a similar fracture in one of our patients on long-term N-BP therapy. Osteonecrosis of the jaw remains the only bone-related complication that had been previously clearly associated with long-term IV N-BP use48.
Although vertebral compression, rib, and proximal long-bone fractures frequently occur in patients with multiple myeloma47,49,50, metatarsal stress fractures have only been observed in our practice in the last several years; many of the patients with these fractures had received N-BPs for five or more years.
Zoledronic acid and pamidronate are both approved for monthly treatment of patients with multiple myeloma and metastatic bone disease7,10-12,51. After receiving long-term monthly treatment with N-BPs, six of our patients experienced a total of eight metatarsal fractures despite the fact that none of them were athletes or engaged in vigorous physical activity (Table II). The total duration of N-BP treatment before our patients developed their first metatarsal fracture was 5.5, 7.5, 7.5, 7.6, 8.8, and eleven years, with a median of 7.55 years. One patient received only pamidronate; the other five patients received zoledronic acid for 3.5, 5.5, 6.8, seven, and 7.5 years, and four of these patients had received pamidronate from 0.8 to four years prior to treatment with zoledronic acid. One patient developed two separate metatarsal fractures, one in each foot, within six months, and another patient experienced two separate metatarsal fractures in the same foot four years apart. The six individuals experiencing these eight fractures were among a relatively small cohort of 300 patients who had received treatment with N-BPs in our practice, and thus these findings are unlikely to be coincidental. Only forty-nine of our patients with multiple myeloma had received N-BPs for more than 5.5 years, the shortest time to the onset of fracture in our six cases. Thus, metatarsal fractures occurred in six (12%) of forty-nine patients receiving N-BPs for ≥5.5 years.
Nearly three-quarters of our patients with multiple myeloma have some degree of peripheral neuropathy, and such patients can unknowingly sustain repeat injuries resulting in stress fractures. However, three of the six patients reported on here showed no evidence of peripheral neuropathy, and the other three had only minimal symptoms of neuropathy.
Other treatments including glucocorticosteroids, which have been reported to increase the incidence of stress fractures, could have contributed to these fractures52. However, while treatment with glucocorticosteroids could have been a contributing factor among our patients who received them, a different etiology must have been present in the two patients who had never received glucocorticosteroids. Furthermore, among the four who had received these drugs, one had not received them for several years prior to the fracture. To the best of our knowledge, there have been no previous reports of metatarsal stress fractures in patients with multiple myeloma despite the widespread use of glucocorticosteroids to treat this disease since the 1960s.
Stress fractures occur as a result of extensive, inadequately repaired microdamage; microdamage can occur in all bones but is generally repaired quickly as bone is turned over36-38. Bisphosphonates interrupt osteoclastic resorption and reduce bone turnover51,53-55. If remodeling is impeded for a long time, bones can become brittle45, microdamage can accumulate, and fractures can occur45. Stress fractures following long-term N-BP use can result because a slowing of bone turnover prevents the repair of routine microfractures that occur with weight-bearing activities56,57. The bilateral occurrence of two separate metatarsal fractures in Case 4 supports this hypothesis rather than the existence of a localized inciting event. Our theory is consistent with a study of subtrochanteric fractures26 in which more than half of the patients sustained a fracture bilaterally.
The benefits of continued IV N-BP therapy for patients with multiple myeloma have been clearly demonstrated in randomized clinical trials10-12. More than 75% of patients have lytic bone lesions or fractures at the time of diagnosis of multiple myeloma, and, without these agents, most patients experience skeletal complications as the disease progresses19,58-60. Bisphosphonate therapy profoundly improves the quality of life of patients with multiple myeloma, permitting them a more active lifestyle by decreasing the risk of skeletal complications10.
Until only a few years ago, the median survival time of patients with multiple myeloma was only two or three years61-63. With this limited overall survival time, complications from long-term N-BPs were not observed. However, with the advent of new therapeutic options within the past five years, patients are living longer and are experiencing fewer skeletal complications18,64. A recent retrospective study19 of patients with multiple myeloma treated with zoledronic acid showed the median survival time to be more than ten years, and skeletal events occurred much less frequently than in prior studies10-12. Monthly zoledronic acid has recently been shown to reduce more skeleton-related problems than daily oral clodronate, and it also improves overall survival time20. These findings are likely to increase the number of patients receiving long-term N-BPs, so we expect that new complications related to the chronic use of these drugs will be identified.
Despite the potential risk of fractures in the metatarsal bones in patients with multiple myeloma who are receiving long-term N-BP therapy, monthly administration remains an important component of treatment. Whether these drugs enhance or impair the fracture-healing process remains the subject of ongoing debate65. Some studies showed that N-BPs adversely affect healing; thus, the authors recommended cessation of N-BP therapy until the fracture has resolved66,67. However, other studies showed that N-BPs can have a positive impact on healing by increasing bone mineralization, volume, strength, and callus size68-71.
Because of the known bone-strengthening and potential anticancer effects of this therapy, we elected to continue monthly treatment with N-BPs for our six patients with these fractures. Our patients had resolution of the fracture-related symptoms (except for Case 1, who continued to have intermittent symptoms at the time of writing) with ongoing monthly N-BP therapy. No patient required surgery, and the fractures were managed effectively with CAM walkers, orthotic devices, and bone-growth stimulators.
The optimal duration of monthly N-BP therapy for patients with multiple myeloma is unknown. With this new potential drug-related complication of metatarsal stress fracture, it is not clear whether it is better to continue treatment or to temporarily or permanently discontinue it after the occurrence of one of these fractures. The recent warning by the U.S. Food and Drug Administration concerning subtrochanteric and diaphyseal fractures after three to five years of continuous therapy was for the treatment of osteoporosis with N-BPs33 and did not apply to monthly IV administration of either zoledronic acid or pamidronate to treat patients with multiple myeloma. Guidelines from both the Mayo Clinic and the International Working Myeloma Group have recommended the discontinuation of N-BP therapy for patients with multiple myeloma after two years if they have stable or responding disease or are not receiving active therapy for the multiple myeloma48,72. The recent results showing reduced skeletal morbidity and a positive impact of N-BPs on the overall survival time of patients with multiple myeloma20 indicate that the discontinuation of these drugs—either after a specific time period or after the occurrence of this type of foot fracture, which healed despite ongoing monthly N-BP treatment in our patients—may not be appropriate. However, it is also possible that discontinuation of N-BP therapy in our patients with metatarsal fractures could have led to a more rapid resolution of their symptoms or could have prevented the occurrence of a second metatarsal fracture in the two patients. The recognition of this fracture pattern among patients on long-term monthly N-BP therapy will hopefully lead to additional studies that address the etiology of these fractures and potential therapeutic maneuvers that can reduce their occurrence and improve patient outcomes.