Metatarsal Stress Fractures in Patients with Multiple Myeloma Treated with Long-Term Bisphosphonates

Waterman, Gabriel N.; Yellin, Ori; Jamshidinia, Kamran; Swift, Regina A.; Tamkin, James; Audell, Robert A; Berenson, James R.

doi:10.2106/jbjs.j.00455

Cited by 13 publications

(7 citation statements)

References 59 publications

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“…For multiple myeloma, most recent consensus guidelines recommend monthly aBP treatment for a period of 2 years (3,4). However, it is unknown whether monthly dosing of aBPs is optimal, as there are consequences of long-term aBP therapy, such as osteonecrosis of the jaw (ONJ) and atypical stress fractures (3)(4)(5)(6)(7)(8)(9). Bisphosphonate-related ONJ is characterized by bone that is necrotic and exposed, located in the maxillofacial area, and present for at least 8 weeks in a patient with history of bisphosphonate treatment, but no history of prior radiation to that area (10).…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Patel

Yee

Scullen

et al. 2014

Clinical Cancer Research

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Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling.Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA.Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients.Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. Clin Cancer Res; 20(15); 3955-61. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Patel

Yee

Scullen

et al. 2014

Clinical Cancer Research

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“…Regarding the reports of MTFs in patients treated for multiple myeloma with BPs [22,23], it is unlikely that the fractures were pathologic lesions secondary to the malignancy. A survey [24] of the Mayo Clinic records of 165 persons with the diagnosis of multiple myeloma treated in the years 1945-2001 (before the use of intravenous BP treatments) found no cases of spontaneous or pathologic MTFs.…”

Section: Resultsmentioning

confidence: 99%

The Atraumatic Metatarsal Fracture: A Clinical Sign of Bisphosphonate-Associated Bone Fragility

Hinshaw¹,

Schneider

2018

JAMPS

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Beginning with some of the earliest publications suggesting the association between bisphosphonate treatment for osteoporosis and coincident skeletal fractures, the wide range of fractured bones reported have included the metatarsals. This paper presents a survey of the medical literature describing this association. Evidence is offered supporting definitions of inclusion rather than exclusion in seeking to define bisphosphonate-associated fractures. In addition we question the recent trend toward attributing fractures of the metatarsal as well as at other sites to "holidays" from bisphosphonate and other strong antiresorptive drugs. A 2018 paper proposed that the increased metatarsal fracture risk that persists years after stopping bisphosphonate therapy may be explained by the cessation of the antiresorptive drug. We propose instead that the frequency of this association justifies the inclusion of a prevalent or subsequent metatarsal fracture as one of the optional minor features defining the bisphosphonate-associated atypical femoral fracture.

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“…33,34 Despite the initial response, prolonged use of aminobisphosphonates often results in osteonecrosis of the jaw and atypical stress fractures. [35][36][37][38][39][40][41] Although the classical pathways activating osteoclast functions are well known in myeloma bone lesions, testing of novel approaches is hampered by a lack of appropriate preclinical models exhibiting adequate window for disease progression with characteristics of disseminated disease in major bones. Toward advancing and testing a genetically engineered stem cell therapy by a systemic approach, targeting osteolytic pathology in myeloma, we first developed a mouse model using the human myeloma cell lines, overexpressing heparanase.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma

Higgs¹,

Lee²,

Wang³

et al. 2017

Blood Advances

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Metatarsal Stress Fractures in Patients with Multiple Myeloma Treated with Long-Term Bisphosphonates

Cited by 13 publications

References 59 publications

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

The Atraumatic Metatarsal Fracture: A Clinical Sign of Bisphosphonate-Associated Bone Fragility

Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma

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