Recent advances in models for screening potential osteoporosis drugs

ABSTRACT

Introduction: Osteoporosis is a growing health and health-economic problem due to the increased proportion of elderly people in the population. Basic and clinical advances in research over the past two decades have led to the development of different compounds with antiresorptive or anabolic activity on bone that improved substantially the management of patients with osteoporosis over calcitonin or estrogen replacement. New compounds are in preclinical and clinical development.

Areas covered: In this review, the authors review the approaches for the preclinical and clinical development of antiresorptive and anabolic agents for osteoporosis, particularly focusing on the recent advances in technology and in the understanding of skeletal biology, together with their implications on novel osteoporosis drug discovery.

Expert opinion: Based on the available evidence from the approved drugs for the treatment osteoporosis as well as from the different compounds under clinical development, it has become clear that long term nonclinical pharmacological studies with either bone quality and off-target effects as the main outcomes should be required for new drugs intended to treat osteoporosis. At the same time, basic and clinical advances in research have underlined the necessity to develop new technologies and new models for a thorough screening of the effects of new drugs on the different components of skeletal aging and bone fragility that cannot be assessed by bone mass measurement.

KEYWORDS:

• Osteoporosis
• fractures
• bone metabolism
• animal models
• skeletal aging
• treatment of osteoporosis

Article highlights

• Osteoporosis is a growing health and health-economic problem, affecting up to 50% postmenopausal women and 20% of men older than 50 years. Basic and clinical advances in research occurred in the past decades have allowed the development of different compounds with antiresorptive or anabolic activity on bone that improved substantially the management of patients with osteoporosis over calcitonin or estrogen replacement.

• Despite the differences in the mechanism of action and the remarkable advances in technology occurred through years, the development of these compounds, from the preclinical to the clinical phase, has been mainly focused on postmenopausal osteoporosis and followed common registrative criteria. These included pharmacology and toxicology studies, animal studies in the OVX mice and at least one additional animal model of different species (e.g. monkeys), and 2–3 years registrative trials on postmenopausal women with osteoporosis.

• The recent progresses in translational medicine have remarkably improved our knowledge on bone biology, thus allowing the identification of multiple pathways and targets for osteoporosis pharmacotherapy. Given the requirement of long term regimens and based on the safety issues emerged with most of the available compounds and the recent withdrawal of new promising agents such as odanacatib (a cathepsin K inhibitor), the future preclinical and clinical development of new chemical entities for osteoporosis should consider a thorough evaluation of their off target effects, possibly over a long-term.

• Even though the OVX mice still represents the most extensively used model for preclinical studies for either antiresorptive or anabolic agents for osteoporosis, it does not completely recapitulate all the hallmarks of bone fragility and recent studies have underlined additional bone-intrinsic mechanisms contributing to skeletal fragility with aging (e.g. cell senescence and oxidative stress), that are at least in part independent from the loss of ovarian function and estrogen deficiency.

• Since cellular senescence and other age-related causes of bone fragility are common to the pathogenesis of other disorders (e.g. diabetes and cardiovascular diseases) it is likely that future pharmacological approaches directly targeting the cellular mechanisms of aging will be developed as a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.