doi:10.1111/imj.13502 POSITION PAPER Bisphosphonate guidelines for treatment and prevention of myeloma bone disease Oi Lin Lee,1 Noemi Horvath,1,2 Cindy Lee,2,3 Doug Joshua,2,4,5 Joy Ho,2,4,5 Jeff Szer ,2,6,7 Hang Quach,2,6,8 Andrew Spencer,2,6,9 Simon Harrison,2,6,10 Peter Mollee,2,11,12 Andrew W. Roberts,2,6,7,13 Dipti Talaulikar,2,14,15 Ross Brown,2,4 Bradley Augustson,2,16 Silvia Ling,2,17,18 Wilfrid Jaksic,2,3 John Gibson,2,4,5 Anna Kalff,2,9 Anna Johnston,2,19,20 Akash Kalro,2,21 Chris Ward,2,5,22 H. Miles Prince2,10,6 and Andrew Zannettino 2,23,24 1Department of Haematology, Royal Adelaide Hospital, 3Department of Haematology, Queen Elizabeth Hospital, 23Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, and 24Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, 2Medical and Scientific Advisory Group, Myeloma Australia, 6Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, 7Department of Clinical Haematology and BMT, Royal Melbourne Hospital, 8Department of Haematology, St Vincent’s Hospital, 9Department of Haematology, The Alfred Hospital, 10Department of Haematology, Peter MacCallum Cancer Centre, and 13Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 4Department of Haematology, Royal Prince Alfred Hospital, 5Department of Cancer and Haematology, Sydney Medical School, University of Sydney, 17Department of Haematology, Liverpool Hospital, 18South Western Sydney Clinical School, University of New South Wales, and 22Department of Medicine, Royal North Shore Hospital, Sydney, New South Wales, 11Department of Haematology, Princess Alexandra Hospital, and 12School of Medicine, University of Queensland, Brisbane, Queensland, 14Department of Haematology, Canberra Hospital, and 15College of Medicine, Biology and Environment, Australian National University, Canberra, Australian Capital Territory, 16Department of Haematology, Sir Charles Gairdner Hospital, Perth, Western Australia, 19Department of Haematology, Royal Hobart Hospital, and 20Faculty of Health, University of Tasmania, Hobart, Tasmania and 21Department of Haematology, Royal Darwin Hospital, Darwin, Northern Territory, Australia Key words Abstract myeloma, bisphosphonate, skeletal-related event (SRE), osteolysis, osteoblast, osteoclast. Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM Correspondence display evidence of myeloma bone disease (MBD), characterised by the formation of Andrew C. W. Zannettino, Adelaide Medical osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly School, Faculty of Health and Medical Sciences, increases the risk of skeletal-related events such as pathologic fracture, spinal cord com- University of Adelaide, Frome Road, Adelaide, pression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activa- SA 5000, Australia. tion of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), Email: [email protected] pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the Received 7 February 2017; accepted standard of care. Pamidronate and zoledronic acid are the most commonly used BP to 15 May 2017. treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD. Introduction significant economic impact.1,2 Moreover, MBD is also associated with a 30% increased risk of mortality.3 Multiple myeloma (MM) is a clonal plasma cell (PC) malignancy characterised by osteolytic bone disease leading to devastating complications including debilitat- Pathophysiology of MBD ing pain, pathological fractures and spinal cord compres- Bone health, under normal physiological conditions, is sion resulting in significant disability. Myeloma bone maintained by a dynamic balance between bone forma- disease (MBD) is observed in more than 80% of patients tion by osteoblasts and bone resorption by osteoclasts during the course of their disease and severely affects and occurs in response to physiological influences and their quality of life, increases morbidity and has a mechanical forces. In MM, this tightly controlled process of bone formation and resorption is disrupted leading to Funding: None. increased osteoclast activity and decreased osteoblast Conflict of interest: None. activity.6,7 Several soluble MM PC-derived factors have 938 Internal Medicine Journal 47 (2017) 938–951 © 2017 Royal Australasian College of Physicians Australian guidelines for bisphosphonate been implicated in promoting bone destruction. Further- International Myeloma Working Group (IMWG) guide- more, factors released by bone resorption further pro- lines recommend that osteoporosis or compression frac- mote MM cell growth perpetuating the vicious cycle of ture alone without the presence of osteolytic lesion is malignant cell expansion and bone destruction. Factors insufficient to meet the criteria. Notably, bone densitom- that influence osteoclast activation include the receptor etry or evidence of increased fluorodeoxyglucose uptake activator of NF-κB ligand (RANKL)/osteoprotegerin on PET without accompanying destructive bone lesions ratio,6,8–10 macrophage inhibitory protein-1α (MIP- are also insufficient to meet the diagnostic criteria of 1α),11,12 IL-613 and tumour necrosis factor-α (TNFα).14 MBD.20 Recently, the IMWG recommended that patients The factors that inhibit osteoblast activity include the with high-risk smouldering MM should be treated as inhibitors of the Wnt signalling pathway such as symptomatic MM based on certain biomarkers of malig- Dickkopf-1 (Dkk-1), soluble-frizzled receptor-like pro- nancy, including more than one focal lesion of at least teins (sFRP) and sclerostin.15–18 5 mm on MRI.20 Focal lesions on MRI indicate bone marrow involvement and not actual bone destruction.22 Definition and diagnosis of MBD MBD is traditionally diagnosed by plain radiograph- based skeletal surveys, which reveal the presence of Recommendations (Table 1) osteolytic bone lesions or osteoporosis with compression 1 Skeletal survey by conventional radiology may be per- fractures that are attributed to the underlying clonal PC formed initially but WBLD-CT or PET/CT should be disorder.19,20 However, a destructive bone lesion needs used to clarify ambiguous radiological findings or if to be at least 1 cm and associated with a loss of at least suspicion of bony disease is high even with negative 50% of the bone mineral content before it can be conventional radiological findings. (Grade A, Level I) detected by plain radiograph.21 Whole body low dose CT 2 MBDisdefined as one or more osteolytic lesions seen (WBLD-CT), PET/CT and whole body MRI (WB-MRI) on conventional radiology, CT (including WBLD-CT) or represent more sensitive imaging modalities for the CT/PET. On CT, lesions have to be ≥5mm.Increased detection of osteolytic lesions. However, if WB-MRI is activity on PET scan without the accompanying destruc- not widely available, MRI of the spine and pelvis will tive bone lesion is not sufficient. (Grade A, Level I) detect approximately 90% of all osteolytic lesions.22 3 In patients with smouldering MM, more than one Most existing guidelines still recommend skeletal sur- focal lesion on MRI at least 5 mm is also an indication vey by conventional radiography as the initial method for treatment. (Grade A, Level I) for the detection of MBD. Other modalities such as 4 Osteoporosis or compression fracture alone without WBLD-CT, MRI or PET/CT are indicated when there is a accompanying osteolytic bone lesion is also insuffi- suspicion of bony disease even if conventional radiogra- cient to meet the criteria. Neither are bone densitome- phy is negative.20,23–25 A systematic review comparing try studies. (Grade A, Level II) conventional imaging with more modern techniques 5 Bone (technecium-99) scintigraphy has no role in the supports the use of WBLD-CT or MRI.26 With the availa- diagnosis of MBD. (Grade A, Level 1) bility and use of more sensitive modalities, the 2014 Table 1 National Health and Medical Research Council grades for recommendation and levels of evidence4,5 Grades of recommendation Levels of evidence A Body of evidence can be trusted to guide practice I Evidence obtained from a systematic review of all relevant randomised controlled trials B Body of evidence can be trusted to guide practice in most II Evidence obtained from at least one properly designed randomised controlled trial situations C Body of evidence provides some support for III-1 Evidence obtained from well-designed pseudo-randomised controlled trials recommendation(s) but care should be taken in its III-2 Evidence obtained from comparative studies with concurrent controls and application allocation not randomised, cohort studies, case-control studies, or interrupted time series with a control group III-3 Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group D Body of evidence