Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

Abstract

Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.

ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia

“…Data from our group and others have demonstrated that bone‐targeted strategies (e.g. antiresorptive treatments) preserve bone and muscle mass in the presence of platinum‐based chemotherapies 70,71 . Additionally, we have previously indicated that use of ACVR2B/Fc preserves muscle and bone in the presence of the commonly used chemotherapy regimen Folfiri 22 .…”

“…antiresorptive treatments) preserve bone and muscle mass in the presence of platinum-based chemotherapies. 70,71 Additionally, we have previously indicated that use of ACVR2B/Fc preserves muscle and bone in the presence of the commonly used chemotherapy regimen Folfiri. 22 However, to our knowledge, this is the first time that ACVR2B/Fc has shown to preserve bone and muscle together in a model of metastatic CRC.…”

MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer

“…An area of cancer cachexia that has been gaining interest is the multi-organ dysfunction that occurs during disease progression. In particular, we and others have shown that bone loss may accompany muscle loss during cancer cachexia and that a disrupted bone–muscle axis may contribute to disease progression [ 12 , 16 , 28 , 29 , 30 ]. Moreover, we recently demonstrated that the formation of C26 LM not only heightens the wasting of skeletal muscle, but also promotes greater bone loss compared to animals bearing subcutaneous tumors [ 12 , 16 ].…”

The Role of Bone in Muscle Wasting

“…Essex et al [ 22 ] reported that treatment with zoledronate, an antiresorptive bisphosphonate, is able to prevent muscle wasting in normal healthy mice given the chemotherapeutic agent cisplatin, while Hain et al [ 23 ] demonstrated similar effects of zoledronate treatment with use of carboplatin in mice with breast cancer metastatic to bone. Both mouse studies showed that chemotherapeutic agents themselves can cause inflammation-induced bone resorption and muscle wasting and it was the bisphosphonate treatment in each case that prevented the bone resorption and preserved the muscle mass.…”