Charles River offers a fully integrated service with a multidisciplinary team of scientists, pathologists, veterinarians, and surgeons to assess the safety and efficacy of drugs and devices that have an intentional or unintentional effect on the musculoskeletal system in both short- and long-term studies. As a developer, you may need bone toxicity studies to move your program forward. This approach allows for the comprehensive evaluation of bone, muscle, and cartilage drug efficacy and safety, as well as orthobiologic applications.
Can we support your complex musculoskeletal studies?
With 25 years of combined bone toxicity experience, allowing our partners to trust us with their unique studies. From exploratory studies to pathological endpoints, our teams are here to fully support biotechnology and pharmaceutical companies. Explore our available capabilities and services.
- Bone toxicology
- Biomechanical strength testing
- Dose range finding to chronic studies
- Juvenile bone toxicology
- Carcinogenesis studies
- Biochemical markers of bone and cartilage turnover
- bone formation markers
- bone-specific alkaline phosphatase
- cartilage degradation
- C-telopeptide (CTxII)
- bone resorption markers
- C-telopeptide (CTxl)
- TRAP 5b
- hormone markers
- bone formation markers
- Gonadectomy-induced bone loss (osteoporosis: OVX and ORX)
- 5/6 nephrectomy
- TPTx (thyroparathyroidectomy)
- Schenk (anti-catabolic agent screen) bone defect
- Osteoarthritis (surgical and chemical models)
- Rheumatoid arthritis
- Spinal fusion and instability/fixation
- Fracture healing and defect repair models
- XtremeCT II
- Digital radiography
- Supportive Services
Frequently Asked Questions (FAQs) about Musculoskeletal Toxicology & Bone Toxicity Studies
What is musculoskeletal toxicology?
Musculoskeletal toxicology is a subdiscipline of toxicology focusing on the detection of any effects of chemical, physical or biological agents on the structure and function of the musculoskeletal system: bone, muscle, cartilage, joints, and tendons.
What drugs affect the musculoskeletal system?
Many drugs can have direct or indirect effects on the musculoskeletal system and cause bone toxicity. Here are several examples, but each year new drugs are added to this list:
- Activin-like kinase inhibitors
- Antidiabetics (e.g., PPAR-gamma agonist, SGLT-2 inhibitors)
- Antiviral (e.g., Tenofovir)
- Aromatase inhibitors
- Beta2-adrenergic agonist (e.g., Clenbuterol)
- Bone morphogenetic proteins (BMPs)
- Bone anabolic agents (e.g., parathyroid hormone and antisclerostin antibodies)
- Bone antiresorptive (e.g., bisphosphonates and Denosumab)
- Farnesoid X receptor (FXR) agonist
- Fibroblast growth factor agonists (e.g., FGF21)
- Fibroblast growth factor receptor 3 antagonists - C-type natriuretic peptide (CNP)
- Gut hormones related drugs (e.g., GLP or GIP/GIPR)
- Janus-activated kinase (JAK) inhibitors
- Orexin neuropeptides
- Proton pump inhibitor (e.g., Omeprazole)
- Retinoids and vitamin A analogues
- Serotonin reuptake inhibitors
- Wnt inhibitors
Another class of drugs can potentially affect the musculoskeletal system:
- Bile metabolism targeting drug (ASBT inhibitors)
- Antibodies targeting calcitonin gene-related peptide (CGRP) or calcitonin receptor (CTR)
- Therapeutic modulation of the complement cascade
- Erythropoietin drugs, gremlin agonists
- Integrin inhibitors
- Lysophosphatidic acid (LPA) agonists and antagonists
- Antihypertensive soluble guanylate cyclase (sGC) agonists
- Triggering receptor expressed in myeloid cells 2 (TREM2)
- Relaxin family peptide agonists
- R-spondin agonists
What outcomes do you look for when conducting musculoskeletal toxicology studies?
There is an extensive toolbox that can be used to assess effects of drugs on the musculoskeletal system. We recommend using a tier approach and the methods used need to be tailored to the study design and objectives. Contact us and we will guide you on how to navigate through the following outcomes:
- Chemical markers of bone turnover
- Physical measurements
- Bone densitometry
- Biomechanical testing
Are musculoskeletal toxicology studies required by regulatory agencies?
If any concern on the musculoskeletal system or bone toxicity comes up during drug development, some of the specific endpoints (chemical markers of bone turnover, physical measurements, radiography, bone densitometry, histomorphometry, or biomechanical testing) will be requested by regulatory agencies to ensure the safety , as specified in US (FDA): Osteoporosis: Nonclinical Evaluation of Drugs Intended for Treatment, Guidance for Industry (Aug 2019) for osteoporosis-related drugs.
Guidance for the assessment of the musculoskeletal system in juvenile studies can be found in US (ICH Harmonized Guideline): Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals (2020).
- US (FDA): Guidance Document: Nonclinical Safety Evaluation of Pediatric Drug Products (2006)
- Europe (EMA): Guideline on the need for Nonclinical Testing in Juvenile Animals on Human Pharmaceuticals for Pediatric Indications (2008)
- Japan (MHLW): Guideline on the Nonclinical Safety Study in Juvenile Animals for Pediatric Drugs (2012)
In addition, here is some other guidance mentioning musculoskeletal specific endpoints:
- Europe (EMA): Guideline on the evaluation of medical products in the treatment of primary osteoporosis (2007)
- Japan (MHLW): Guidelines on Clinical Evaluation of Drugs to Treat Osteoporosis (Notification No. 742 of the Evaluation and Licensing Division, PMSB dated April 15, 1999)