Case Report of Spontaneous, Nonspinal Fractures in a Multiple Myeloma Patient on Long-term Pamidronate and Zoledronic Acid
- First Online:
- Cite this article as:
- Wernecke, G., Namduri, S., DiCarlo, E.F. et al. HSS Jrnl (2008) 4: 123. doi:10.1007/s11420-008-9077-4
Pamidronate and zoledronic acid are two potent intravenous bisphosphonates used in the treatment of multiple myeloma as well as osteoporosis. While the concern for heightened fracture risk in a patient on long-term bisphosphonate treatment for malignancy has been previously noted, we present the first case of spontaneous, nonspinal fractures in a patient undergoing treatment for multiple myeloma. The patient had a positive 9-year history of bisphosphonate treatment and presented with sequential subtrochanteric stress fractures of the left and right femurs. Pathological reports of fracture site biopsies demonstrate signs consistent with ametabolic bone and no malignancy. These findings point to extreme inhibition of bone turnover by bisphosphonates as the cause of this patient’s morbidity. This is a single retrospective case study (level IV evidence).
Keywordslong-term bisphosphonate therapystress fracturemultiple myelomaosteoporosis
Multiple myeloma, a malignant plasma cell disease, results in heightened osteoclastic activity and in turn osteoporosis, lytic bone disease, and skeletal fractures. Bisphosphonates have become a standard part of treatment for the cancer-induced hypercalcemia and osteoporosis. By inhibiting the action of osteoclasts and preventing bone resorption, bisphosphonates have been shown to reduce bony complications and fractures in patients with multiple myeloma [1–7]. In addition, by limiting endosteal resorption, bone marrow expansion of myeloma cells may be inhibited. Zoledronic acid is a nitrogen-containing bisphosphonate that inhibits enzymes of the mavelonate pathway and consequently inhibits prenylation of small guanosine triphosphate-binding proteins, which eventually leads to secondary osteoclast apoptosis [8–11]. Due to its high potency, this bisphosphonate has become the first option in the treatment of malignancy-induced hypercalcemia and osteoporosis. Its efficacy and safety have been demonstrated in randomized clinical trials using breast cancer, multiple myeloma [12–13], lung cancer, and prostate cancer patients .
While oral bisphosphonates have a long history of successful use in the treatment of nonmalignancy-associated osteoporosis, recent concern has arisen regarding the potential side effects of long-term use. Sustained inhibition of bone turnover leads to brittle bone due to increased mineralization and progressive microdamage that is not repaired or remodeled [15–22]. These studies have led to a concern that sustained inhibition of osteoclasts may lead to insufficient bone repair and therefore an increase in microdamage accumulation and reduction of bone quality.
There currently exists no long-term (>5-year) study that has examined the intrinsic skeletal effects of bisphosphonates in multiple myeloma patients where the bisphosphonate dosage is more than ten times the dose used in the treatment of osteoporosis. We present the first case of unusual, spontaneous bilateral subtrochanteric fractures in a multiple myeloma patient on long-time pamidronate and zoledronic acid while under complete remission.
Useful laboratory values available from 2001 to present demonstrating course of low to moderate calcium levels and suppressed bone metabolic activity (NTX and bone-specific alkaline phosphatase)
Bone alkaline phosphatase
Multiple clinical trials show the efficacy and safety of bisphosphonates in improving bone mass density and reducing fracture risk in multiple myeloma and osteoporotic patients. However, there are no studies beyond 10 years of treatment and no studies that show continued reduction in fracture risk after 5 years of treatment. The possibility of heightened fracture risk in patients on long-term bisphosphonates has been considered in the past [23–25]. Another possibility is the adverse effect of other anticancer agents on bone turnover. However, there are some reports in the literature of fracture and delayed healing in otherwise healthy patients not receiving chemotherapy. Odvina et al. reported on nine patients who sustained spontaneous, nonspinal fractures while on alendronate therapy . Six of these patients displayed delayed or absent fracture healing. Iliac crest bone biopsies in all nine patients revealed severe depression of bone formation with absence of double-tetracycline labeling. Schneider et al. reported a case of a previously healthy woman who experienced two nontraumatic stress fractures, 4 years apart, while on alendronate therapy for approximately 7 years . This patient went on to suffer a delayed union of a spiral femoral fracture that resulted from the stress fracture. Both fractures healed after several months of stopping bisphosphonate treatment.
The therapeutic goal in medical treatment of multiple myeloma with bisphosphonates has been both to target osteoclast-mediated bone disease, including hypercalcemia of malignancy, bone metastases, and osteoporosis, and to gain additional antitumor effects. However, this class of drugs does not go without side effects including hypocalcemia, injection site reaction, flu-like syndrome, renal toxicity, ocular complications, and recently, numerous reports of osteonecrosis of the jaw [28–29]. Based on these risks and uncertainties, the Mayo Clinic Consensus Statement for Bisphosphonates in Multiple Myeloma recommends the cessation of bisphosphonate use if the patient has achieved response and is in a stable plateau phase of treatment .
Pamidronate and zoledronic acid are two potent intravenous bisphosphonates used in the treatment of multiple myeloma as well as osteoporosis. While the concern for heightened fracture risk in a patient on long-term bisphosphonate treatment for malignancy has been previously noted, we present the first case of spontaneous, nonspinal fractures in a patient undergoing treatment for multiple myeloma. Though it is possible for these fractures to have been pathologic due to our patient’s underlying disease, we have imaging studies as well as gross and micropathological bone biopsies from the fracture sites showing complete remission from her multiple myeloma. These fractures could also be osteoporotic insufficiency fractures; however, their unusual locations and the patient’s improved bone mass density and normal laboratory values indicate a different type of pathology. The pathology in this patient demonstrated decreased cellular activity on the cancellous bone surfaces, indicating decreased bone metabolism. This decrease in cellular activity renders the bone incapable of responding to normal microdamage, eventually leading to stress fractures. The delays in the healing of both fractures, extending well beyond the cessation of bisphosphonate treatment, are likely a repercussion of both the potency and highly absorptive nature of zoledronic acid in the bone. This case raises concerns about the long-term suppression of bone turnover with large doses of intravenous bisphosphonates.