Orthopedics

Pharmacology Update 

Complications Associated with Treatment of Malignancies: A Focus on Avascular Necrosis of the Bone

Ashley M. Newland, PharmD; Amber P. Lawson, PharmD, BCOP; Val R. Adams, PharmD, FCCP, BCOP

Abstract

Drs Newland and Lawson are from University of Kentucky HealthCare, and Dr Adams is from University of Kentucky College of Pharmacy, Lexington, Kentucky.

Drs Newland, Lawson, and Adams have no relevant financial relationships to disclose.

Correspondence should be addressed to: Ashley M. Newland, PharmD, Department of Pharmacy Services, University of Kentucky HealthCare, 800 Rose St, H110, Lexington, KY 40536-0293 (ashley.newland@uky.edu).

Cancer patients have a better prognosis now than in the past. An estimated 66% of patients diagnosed with cancer between 1996 and 2004 were alive at 5 years.1 As patients are living longer after treatment, long-term complications associated with treatment are becoming a greater issue. Avascular necrosis, also referred to as osteonecrosis, ischemic necrosis, subchondral avascular necrosis, aseptic necrosis of bone, and osteochondritis dissecans, is one such complication.2

Avascular necrosis is a disorder involving breakdown of the bone and has been reported as a complication associated with a number of different disease states and drug therapies. Joint replacement surgery may be required in cases of severe bone destruction, and avascular necrosis has been reported to be the cause for >10% of joint replacement procedures in the United States.2

Chemotherapy agents and other medications used in the treatment of malignancy have been associated with the development of avascular necrosis, including corticosteroids, bisphosphonates, asparaginase, and others (Sidebar). It is important to be aware of these potential drug causes of avascular necrosis, as early recognition and management of the disease process, including early cessation of causative therapy, is necessary to improve patient outcomes, reduce morbidity, and improve quality of life.2

Corticosteroids

Bisphosphonates

Chemotherapy agents

Asparaginase

Bleomycin

Cyclophosphamide

Docetaxel

Doxorubicin

Fluorouracil

Methotrexate

Paclitaxel

Thalidomide

Vinblastine

Abbreviation: AVN, avascular necrosis.

Avascular necrosis is a pathological process involving death of bone and bone marrow cells secondary to compromise of the bone vasculature and blood flow. With interrupted blood flow, osteocytes and fat cells die, leading to marrow edema and changes in bone structure.3 This leads to infarction and death of bone, causing the collapse of the architectural structure of the bone and mechanical failure.2 Avascular necrosis most commonly occurs in weight-bearing joints such as the hips, knees, humeral head, and jaw.3,4 Although the exact mechanism for development of avascular necrosis is unknown, several mechanisms have been proposed, including vascular occlusion, altered lipid metabolism and fat emboli, intravascular coagulation, healing processes, and primary cell death.2 In cancer patients, hypercoagulability is thought to be an important contributing factor to develop avascular necrosis.5

Symptoms associated with avascular necrosis include pain at the injury site, swelling, and limited range of motion. Pain may start as mild but can progress rapidly to severe pain in situations involving avascular necrosis secondary to trauma. Range of motion is generally not an issue initially, but as the disease progresses, it can lead to functional limitations.

A number of causes of avascular necrosis, including local trauma, hematologic disorders, metabolic abnormalities, chronic renal failure, pancreatitis, and infectious processes such as osteomyelitis. Alcoholism and tobacco abuse have also been tied to increased risk of avascular necrosis.3

Orthopedic problems such as congenital hip dislocation, slipped capital femoral epiphysis, hereditary dysostosis, and Legg-Calve-Perthes disease have also been associated with avascular necrosis. Iatrogenic causes of avascular necrosis include radiation, hemodialysis, organ transplantation, and medications.2

Drug therapies used for the treatment of malignancies have been implicated in the occurrence of avascular necrosis, with corticosteroids being the most widely reported medication. Patients with existing risk factors for avascular necrosis who are receiving drug therapy associated with avascular necrosis are at an increased risk of developing avascular necrosis compared to patients without preexisting risk. Cancer patients commonly fit into this multiple avascular necrosis…

Drs Newland and Lawson are from University of Kentucky HealthCare, and Dr Adams is from University of Kentucky College of Pharmacy, Lexington, Kentucky.

Drs Newland, Lawson, and Adams have no relevant financial relationships to disclose.

Correspondence should be addressed to: Ashley M. Newland, PharmD, Department of Pharmacy Services, University of Kentucky HealthCare, 800 Rose St, H110, Lexington, KY 40536-0293 (ashley.newland@uky.edu).

Cancer patients have a better prognosis now than in the past. An estimated 66% of patients diagnosed with cancer between 1996 and 2004 were alive at 5 years.1 As patients are living longer after treatment, long-term complications associated with treatment are becoming a greater issue. Avascular necrosis, also referred to as osteonecrosis, ischemic necrosis, subchondral avascular necrosis, aseptic necrosis of bone, and osteochondritis dissecans, is one such complication.2

Avascular necrosis is a disorder involving breakdown of the bone and has been reported as a complication associated with a number of different disease states and drug therapies. Joint replacement surgery may be required in cases of severe bone destruction, and avascular necrosis has been reported to be the cause for >10% of joint replacement procedures in the United States.2

Chemotherapy agents and other medications used in the treatment of malignancy have been associated with the development of avascular necrosis, including corticosteroids, bisphosphonates, asparaginase, and others (Sidebar). It is important to be aware of these potential drug causes of avascular necrosis, as early recognition and management of the disease process, including early cessation of causative therapy, is necessary to improve patient outcomes, reduce morbidity, and improve quality of life.2

Oncology Agents Associated with Avascular Necrosis

Corticosteroids

Bisphosphonates

Chemotherapy agents

  • Asparaginase

  • Bleomycin

  • Cyclophosphamide

  • Docetaxel

  • Doxorubicin

  • Fluorouracil

  • Methotrexate

  • Paclitaxel

  • Thalidomide

  • Vinblastine

Abbreviation: AVN, avascular necrosis.

Pathophysiology of Avasular Necrosis

Avascular necrosis is a pathological process involving death of bone and bone marrow cells secondary to compromise of the bone vasculature and blood flow. With interrupted blood flow, osteocytes and fat cells die, leading to marrow edema and changes in bone structure.3 This leads to infarction and death of bone, causing the collapse of the architectural structure of the bone and mechanical failure.2 Avascular necrosis most commonly occurs in weight-bearing joints such as the hips, knees, humeral head, and jaw.3,4 Although the exact mechanism for development of avascular necrosis is unknown, several mechanisms have been proposed, including vascular occlusion, altered lipid metabolism and fat emboli, intravascular coagulation, healing processes, and primary cell death.2 In cancer patients, hypercoagulability is thought to be an important contributing factor to develop avascular necrosis.5

Symptoms associated with avascular necrosis include pain at the injury site, swelling, and limited range of motion. Pain may start as mild but can progress rapidly to severe pain in situations involving avascular necrosis secondary to trauma. Range of motion is generally not an issue initially, but as the disease progresses, it can lead to functional limitations.

Etiology of Avascular Necrosis

A number of causes of avascular necrosis, including local trauma, hematologic disorders, metabolic abnormalities, chronic renal failure, pancreatitis, and infectious processes such as osteomyelitis. Alcoholism and tobacco abuse have also been tied to increased risk of avascular necrosis.3

Orthopedic problems such as congenital hip dislocation, slipped capital femoral epiphysis, hereditary dysostosis, and Legg-Calve-Perthes disease have also been associated with avascular necrosis. Iatrogenic causes of avascular necrosis include radiation, hemodialysis, organ transplantation, and medications.2

Drug therapies used for the treatment of malignancies have been implicated in the occurrence of avascular necrosis, with corticosteroids being the most widely reported medication. Patients with existing risk factors for avascular necrosis who are receiving drug therapy associated with avascular necrosis are at an increased risk of developing avascular necrosis compared to patients without preexisting risk. Cancer patients commonly fit into this multiple avascular necrosis risk factor category with associations documented in acute myeloid leukemia, acute lymphoblastic leukemia, lymphomas, testicular cancer, ovarian cancer, breast cancer, and multiple myeloma.5

Incidence of Avascular Necrosis in Cancer Patients During and After Therapy

The incidence of avascular necrosis in cancer patients is not well studied, particularly when investigating specific agents. One of the main factors limiting the research is the retrospective nature of most studies, which presumably misses patients with no or mild symptoms. Despite the limited data, the prevalence of avascular necrosis with corticosteroids has been reported anywhere between 3% and 52%.6 Avascular necrosis has been reported to occur in 1% to 10% of patients receiving chemotherapy or radiation therapy.6 The incidence in pediatric patients treated for high-risk acute lymphoblastic leukemia has been reported to be similar; however, disease risk category appears to influence the risk of avascular necrosis.7 Although the incidence data are variable, it appears clear that given the hundreds of thousands of cancer patients treated each year, this treatment complication is relatively common.

Medications Used in the Treatment of Cancer Associated with Avascular Necrosis

Corticosteroids

Steroids are the second most common cause of avascular necrosis next to trauma and are commonly used in the treatment of acute lymphoblastic leukemia, lymphomas, testicular cancer, and ovarian cancer, and as an adjunctive therapy following hematopoietic stem cell transplant.2 The mechanism of action associated with corticosteroids and development of avascular necrosis is unclear, but several effects could describe the pathogenesis.

Corticosteroids can increase osteoblast apoptosis, leading to a decrease in bone formation and bone density. Increased osteoclast apoptosis in metaphyseal cortical bone has also been demonstrated, which leads to a decrease in bone turnover.2 It is postulated that the accumulation of apoptotic osteocytes may contribute to osteonecrosis.2 Corticosteroids have also been shown to increase coagulation protein concentrations.5 The attribution to each of these pathways is unknown, but collectively the increased risk with corticosteroids is well documented.

The onset of steroid-associated symptomatic avascular necrosis varies. Retrospective studies report that the onset of avascular necrosis symptoms typically occurs >6 months after steroid administration and has been reported to occur >3 years after steroid administration.3 Prospective studies have demonstrated a shorter interval between steroid administration and development of avascular necrosis.3 Prospective studies that involve regular screening reveal that imaging changes of the bone typically occur before the onset of pain, which can explain why avascular necrosis is identified earlier in prospective studies.3

The length of treatment with steroids is also an important factor to consider, as it appears the risk of avascular necrosis with steroids is cumulative, and risk decreases after cessation of steroid treatment.2 It is more common for patients receiving long treatment courses of steroids to develop avascular necrosis, although there are reports of avascular necrosis in patients who received a short treatment course. A review showed an increase in risk of avascular necrosis with increasing total daily doses of steroids, with a 4.6% increase in risk of avascular necrosis for every 10 mg/day increase in prednisone.8 This review also demonstrated an increased risk with oral steroids compared to parenteral steroids.8 Long-acting steroids may also increase the risk of avascular necrosis as opposed to shorter acting steroids. Non-systemic steroid treatments including intra-articular steroid injections and steroid enemas have been reported to cause avascular necrosis, although this is less common.2

Asparaginase in Combination with Corticosteroids

Patients with acute lymphoblastic leukemia commonly receive treatment regimens containing corticosteroids and asparaginase. Although the exact mechanism for the cause of avascular necrosis with asparaginase remains unknown, it has been speculated that asparaginase may interrupt osseous blood supply, leading to avascular necrosis.9

A study investigating whether alterations in coagulation are associated with avascular necrosis in pediatric acute lymphoblastic leukemia found that dexamethasone leads to an increase in the anticoagulants antithrombin and protein S.5 After administration of asparaginase, a decline in the levels of these anticoagulants below normal levels induces a hypercoagulable state and is a potential cause of avascular necrosis.5 Clinical pediatric studies evaluating dexamenthasone and asparaginase have reported avascular necrosis rates >6%.10

A retrospective review of adult patients with acute lymphoblastic leukemia reported avascular necrosis in 32% of patients who received intensification therapy, which included dexamethasone and asparaginase.11 The authors speculated that the high doses of corticosteroids could have led to increased rates of avascular necrosis, which may have been further exacerbated by the use of asparaginase.

Bisphosphonates

Bisphosphonates are a class of medications commonly used as an adjunct therapy in patients with certain solid malignancies and multiple myeloma. Bisphosphonates primarily work by inhibition of osteoclastic bone resorption. It has also been shown that bisphosphonates have anti-angiogenic potential and cause a decrease in vascular endothelial growth factor.12 The anti-angiogenesis effects may be an additional contributing mechanism to the development of avascular necrosis. Numerous case reports exist of avascular necrosis secondary to bisphosphonate use, with the majority of the cases involving the mandible or maxilla.12–14 The majority of patients had prior chemotherapy and steroids, but the most common finding is recent dental procedures including tooth extraction. Dental procedures and surgery should be avoided if possible in patients receiving bisphosphonates. For patients who need a dental procedure while receiving a bisphosphonate, it is unclear if stopping therapy will reduce the risk of osteonecrosis.15

Chemotherapy

Although avascular necrosis may be attributed to steroids in the oncology population, several case reports and case series in the literature also suggest chemotherapeutic agents may play a role in the development of avascular necrosis (Sidebar).4,6,7,9,16–23

Management of Avascular Necrosis

Avascular necrosis can be managed by surgical or pharmacological treatment options. Goals of avascular necrosis management are typically palliative, as there is currently no proven treatment available to stop progression of the disease.2,3

Preferred treatment is determined by the severity of the disease at the time of presentation, the size and location of the lesion, and demographic factors such as patient age and overall health. Pharmacologic options include analgesia and discontinuation of any offending agents such as steroids. Surgical options include joint reconstruction, core decompression, bone grafting, and osteotomy.1

Avascular necrosis can potentially be prevented by recognition of predisposing risk factors for avascular necrosis before starting patients on treatment with medications known to cause avascular necrosis. Studies have been conducted to investigate pharmacologic prevention measures such as calcium and statins, although results remain inconclusive and additional studies are warranted.3 No clear guidelines or recommendations are available for prevention of avascular necrosis.

References

  1. 2009 Cancer Facts and Figures. American Cancer Society Web site. http://www.cancer.org/downloads/STT/500809web.pdf. Accessed April 15, 2010.
  2. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002; 32(2):94–124.
  3. Weldon D. The effects of corticosteroids on bone: osteonecrosis (avascular necrosis of the bone). Ann Allergy Asthma Immunol. 2009; 103(2):91–97. doi:10.1016/S1081-1206(10)60159-7 [CrossRef]
  4. Hui L, Wiernik PH. Avascular necrosis of bone after adult acute lymphocytic leukemia treatment with methotrexate, vincristine, L-asparaginase, and dexamethasone (MOAD). Am J Hematol. 1996; 52(3):184–188. doi:10.1002/(SICI)1096-8652(199607)52:3<184::AID-AJH8>3.0.CO;2-P [CrossRef]
  5. te Winkel ML, Appel IM, Pieters R, van den Heuvel-Eibrink MM. Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia. Haematologica. 2008; 93(10):1570–1574. doi:10.3324/haematol.12956 [CrossRef]
  6. Gogas H, Fennelly D. Avascular necrosis following extensive chemotherapy and dexamethasone treatment in a patient with advanced ovarian cancer: case report and review of the literature. Gynecol Oncol. 1996; 63(3):379–381. doi:10.1006/gyno.1996.0339 [CrossRef]
  7. Murphy RG, Greenberg ML. Osteonecrosis in pediatric patients with acute lymphoblastic leukemia. Cancer. 1990; 65(8):1717–1721. doi:10.1002/1097-0142(19900415)65:8<1717::AID-CNCR2820650809>3.0.CO;2-B [CrossRef]
  8. Felson DT, Anderson JJ. Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet. 1987; 1(8538):902–906. doi:10.1016/S0140-6736(87)92870-4 [CrossRef]
  9. Hanada T, Horigome Y, Inudoh M, Takita H. Osteonecrosis of vertebrae in a child with acute lymphocytic leukaemia during L-asparaginase therapy. Eur J Pediatr. 1989; 149(3):162–163. doi:10.1007/BF01958270 [CrossRef]
  10. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009; 360(26):2730–2741. doi:10.1056/NEJMoa0900386 [CrossRef]
  11. Storring JM, Minden MD, Kao S, et al. Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. Br J Haematol. 2009; 146(1):76–85. doi:10.1111/j.1365-2141.2009.07712.x [CrossRef]
  12. Pires FR, Miranda A, Cardoso ES, et al. Oral avascular bone necrosis associated with chemotherapy and bisphosphonate therapy. Oral Dis. 2005; 11(6):365–369. doi:10.1111/j.1601-0825.2005.01130.x [CrossRef]
  13. Lenz JH, Steiner-Krammer B, Schmidt W, Fietkau R, Mueller PC, Gundlach KK. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates?J Craniomaxillofac Surg. 2005; 33(6):395–403.
  14. Bagan JV, Murillo J, Jimenez Y, et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med. 2005; 34(2):120–123. doi:10.1111/j.1600-0714.2004.00269.x [CrossRef]
  15. Gebara SN, Moubayed H. Risk of osteonecrosis of the jaw in cancer patients taking bisphosphonates. Am J Health Syst Pharm. 2009; 66(17):1541–1547. doi:10.2146/ajhp080251 [CrossRef]
  16. Solarino G, Scialpi L, Bruno M, De Cillis B. On a case of multi-focal osteonecrosis in a patient suffering from acute lymphoblastic leukemia. Chir Organi Mov. 2008; 92(2):119–122. doi:10.1007/s12306-008-0047-2 [CrossRef]
  17. Wei SY, Esmail AN, Bunin N, Dormans JP. Avascular necrosis in children with acute lymphoblastic leukemia. J Pediatr Orthop. 2000; 20(3):331–335. doi:10.1097/00004694-200005000-00012 [CrossRef]
  18. Sawicka-Zukowska M, Kajdas L, Muszynska-Roslan K, Krawczuk-Rybak M, Sonta-Jakimczyk D, Szczepanski T. Avascular necrosis—an anti-neoplastic-treatment-related toxicity: the experiences of two institutions. Pediatr Hematol Oncol. 2006; 23(8):625–629. doi:10.1080/08880010600909938 [CrossRef]
  19. Mascarin M, Giavitto M, Zanazzo GA, et al. Avascular necrosis of bone in children undergoing allogeneic bone marrow transplantation. Cancer. 1991; 68(3):655–659. doi:10.1002/1097-0142(19910801)68:3<655::AID-CNCR2820680336>3.0.CO;2-V [CrossRef]
  20. Cook AM, Dzik-Jurasz AS, Padhani AR, Norman A, Huddart RA. The prevalence of avascular necrosis in patients treated with chemotherapy for testicular tumours. Br J Cancer. 2001; 85(11):1624–1626. doi:10.1054/bjoc.2001.2155 [CrossRef]
  21. Harper PG, Trask C, Souhami RL. Avascular necrosis of bone caused by combination chemotherapy without corticosteroids. Br Med J (Clin Res Ed). 1984; 288(6413):267–268. doi:10.1136/bmj.288.6413.267 [CrossRef]
  22. Ghosh J, Manjunatha YC, Thulkar S, Bakhshi S. Avascular necrosis of femoral head in childhood acute myeloid leukemia: complication of chemotherapy without steroids. Pediatr Blood Cancer. 2008; 51(2):308–309. doi:10.1002/pbc.21559 [CrossRef]
  23. Sung EC, Chan SM, Sakurai K, Chung E. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dentist. 2002; 22(4):142–146. doi:10.1111/j.1754-4505.2002.tb01178.x [CrossRef]

Corticosteroids, the second most common cause of avascular necrosis, are a primary treatment for nearly all hematologic malignancies and are used in essentially all solid tumor patients to prevent or treat toxicities (eg, nausea and vomiting).

Oncology Agents Associated with Avascular Necrosis

Corticosteroids

Bisphosphonates

Chemotherapy agents

  • Asparaginase

  • Bleomycin

  • Cyclophosphamide

  • Docetaxel

  • Doxorubicin

  • Fluorouracil

  • Methotrexate

  • Paclitaxel

  • Thalidomide

  • Vinblastine

Abbreviation: AVN, avascular necrosis.

  • Patients with cancer are living longer, and the early identification and proper management of complications is important to improve outcomes and quality of life.
  • The cause of avascular necrosis is likely multifactorial in patients receiving chemotherapy, and the true incidence of this complication remains unknown.
  • Chemotherapy and medications used as an adjunct to chemotherapy have been associated with the development of avascular necrosis, with the most significant cause being the use of high-dose corticosteroids.
  • If possible, the causative agent should be discontinued.
  • Treatment options for avascular necrosis include surgical or pharmacological treatments, with palliation as the primary goal of management.

The Bottom Line

Authors

Drs Newland and Lawson are from University of Kentucky HealthCare, and Dr Adams is from University of Kentucky College of Pharmacy, Lexington, Kentucky.

Drs Newland, Lawson, and Adams have no relevant financial relationships to disclose.

Correspondence should be addressed to: Ashley M. Newland, PharmD, Department of Pharmacy Services, University of Kentucky HealthCare, 800 Rose St, H110, Lexington, KY 40536-0293 (ashley.newland@uky.edu).

10.3928/01477447-20100429-22

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