Abstract
Background
Approximately 70% of multiple myeloma patients develop pathologic fractures. Osteoclast inhibitors can provide reduction in vertebral fractures with an increased risk of osteonecrosis of the jaw (ONJ). ONJ associated with currently used osteoclast inhibitors causes significant morbidity, often from delayed diagnosis and ineffective treatment.
Methods
The TriNetX Diamond Network was used to create patient cohorts for each medication: alendronate, pamidronate, zoledronic acid, and denosumab. All patients had a diagnosis of multiple myeloma as identified by International Classification of Disease–10 (ICD-10) code C90.0. Pamidronate, zoledronic acid, and denosumab were each compared to alendronate for 5-year incidence of pathologic vertebral fracture (ICD-10 M48.50XA) and development of ONJ.
Results
The 5-year risk of pathologic vertebral fracture was not statistically different between alendronate versus pamidronate, zoledronic acid, and denosumab. However, the 5-year risk of ONJ was significantly higher for both zoledronic acid and denosumab (relative risk 4.85 and 2.9, respectively).
Conclusion
This study shows that fracture reduction risk is comparable for all four treatments in multiple myeloma patients, but ONJ risk is lowest for alendronate and pamidronate. Overall, these data support the continued use of pamidronate and alendronate in multiple myeloma patients.
Keywords: Alendronate, bisphosphonates, denosumab, multiple myeloma, osteoclast inhibitors, osteonecrosis, pamidronate, zoledronic acid
More than 35,730 new cases of multiple myeloma (MM) are diagnosed in the United States annually, with 12,590 deaths attributable to MM.1 MM is the leading cause of destructive bone disease, with 70% of patients developing pathologic fractures, most notably in the spine.2,3 These patients have a greatly reduced quality of life due to common skeletal morbidities such as pathologic vertebral fractures, osteolytic lesions, and bone pain.4 Osteoclast inhibitors can provide reduction of these fractures by mitigating excessive bone resorption. This has led to their widespread adoption in MM patients but with an increased risk of osteonecrosis of the jaw.5–8 Currently used osteoclast inhibitors include bisphosphonates and RANK ligand inhibitors.7–9 Despite their different mechanisms of action, these medications reduce skeletal-related events such as fractures and pain in patients with MM.10,11 However, ONJ associated with these medications causes significant morbidity, often from delayed diagnosis and ineffective treatment.5 We designed this study to evaluate the 5-year risk of ONJ with use of the following treatments: alendronate, pamidronate, zoledronic acid, and denosumab.
METHODS
The TriNetX Diamond Network was used for this study. TriNetX provides access to anonymized medical record information on more than 213 million patients in 92 large health care organizations. Four patient cohorts were created for this study, all of whom had a diagnosis of MM as identified by International Classification of Disease–10 (ICD-10) code C90.0. All patients were also excluded from having a prior diagnosis of osteonecrosis of the jaw by ICD-10 M87.180. One cohort was created for each fracture-reduction medication: alendronate, pamidronate, zoledronic acid, and denosumab. The cohorts each included at least 5400 patients and were balanced for age, race, gender, and ethnicity. Pamidronate, zoledronic acid, and denosumab were each compared to alendronate with regard to the 5-year incidence of pathologic vertebral fracture (ICD-10 M48.50XA) and development of osteonecrosis of the jaw.
RESULTS
The 5-year risk of pathologic vertebral fracture was not statistically different between the comparisons of alendronate versus pamidronate, zoledronic acid, and denosumab (Table 1). However, the 5-year risk of developing osteonecrosis of the jaw was significantly higher for both zoledronic acid and denosumab (relative risk 4.85 and 2.9, respectively). The risk of ONJ for pamidronate was not statistically significant compared to alendronate (Table 2).
Table 1.
Risk of pathologic vertebral fracture for each medication compared to alendronate
| Medication | Five-year risk | Risk ratio | 95% CI | P value |
|---|---|---|---|---|
| Pamidronate | 3.40% | 0.92 | 0.68, 1.26 | 0.6 |
| Zoledronic acid | 2.69% | 0.93 | 0.78, 1.11 | 0.4 |
| Denosumab | 1.62% | 1.06 | 0.79, 1.43 | 0.7 |
Table 2.
Risk of osteonecrosis of the jaw for each medication compared to alendronate
| Medication | Five-year risk | Risk ratio | 95% CI | P value |
|---|---|---|---|---|
| Pamidronate | 0.63% | 1.4 | 0.62, 3.15 | 0.41 |
| Zoledronic acid | 1.08% | 4.9 | 3.0, 7.8 | <0.001 |
| Denosumab | 0.54% | 2.9 | 1.42, 5.95 | 0.002 |
DISCUSSION
MM is a malignant neoplastic plasma cell disorder with monoclonal proliferation of malignant plasma cells in the bone marrow. These proliferations frequently result in dispersed osteolytic bone lesions and skeletal destruction.12 Up to 80% of patients with MM will experience a pathologic fracture, particularly of the axial skeleton, over the course of their disease.13 These fractures produce a reduced quality of life with debilitating bone pain and systemic implications such as renal failure, hypercalcemia, and spinal cord compression, leading to poorer clinical outcomes.14,15 Furthermore, the risk of death among patients with MM who experience fractures is twofold that of those without a fracture during their disease progression.16,17 The extensive use of osteoclast inhibitors to treat bone resorption due to MM has led to further discussion regarding their role in fracture reduction and risk of ONJ.5 The severity of ONJ can vary from asymptomatic to severe lesions with clinical symptoms including pain, ulceration of the oral mucosa, and loose teeth.18 Prophylaxis and the preventive measures for ONJ—education of the patient about potential adverse effects associated with the therapy, early detection, and a consistent oral hygiene program—are crucial.19
This study shows that vertebral fracture reduction risk is comparable for all four treatments in MM patients, but ONJ risk is lowest for alendronate and pamidronate. The use of an oral bisphosphonate such as alendronate is considered less aggressive than intravenous therapy, but the osteonecrosis caused by oral bisphosphonate responds better to treatment.20 Overall, the data support the continued use of pamidronate and alendronate in MM patients.
DISCLOSURE STATEMENT
The authors report no funding or conflicts of interest.
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