In search for ‘perfect’ osteoporosis treatment, consider key anti-aging mechanism
BOSTON — A fundamental aging mechanism that drives tissue dysfunction throughout the body may serve as a novel target in the treatment of osteoporosis, suggesting an exciting new pathway for researchers in a field where a “perfect” therapy has remained elusive, according to a speaker at the American Association of Clinical Endocrinologists annual meeting.
The “therapeutic arsenal” for osteoporosis has expanded dramatically since the early 1980s, when the only options were estrogen for women and calcium and vitamin D for men, Sundeep Khosla, MD, director of the Center for Clinical and Translational Science at Mayo Clinic, said during a plenary presentation here. Today, he said, and the picture is much different: Available therapies include estrogen, raloxifene, four different bisphosphonates, the anabolics teriparatide and abaloparatide, the monoclonal antibody denosumab, and perhaps soon, romosozumab, a humanized monoclonal antibody that targets sclerostin.
“The paradigm for drug development has shifted from observational and opportunistic to pathway-based, driven by fundamental bone biology and sometimes by rare bone diseases,” Khosla said during his presentation. “This is a great example of how investing by NIH and by pharma into fundamental discovery science really does translate to novel therapeutics.”
But for all the progress made in osteoporosis research, there are still big challenges to confront, Khosla said — namely, convincing patients that the available therapies are as safe as they are effective. Khosla cited a front-page New York Times report from June 2016 that noted many people opted to forgo osteoporosis therapy due to the small possibility of rare side effects, like atypical femur fractures or osteonecrosis of the jaw. Yet, the number of women who will experience a fracture in 1 year exceeds the combined number of women who will experience incident breast cancer, myocardial infarction or stroke across all ethnic groups, Khosla said.
“We made all this progress, and yet there are many patients who need treatment who are not being treated,” Khosla said. “It’s still a huge public health problem.”
There are important gaps in the therapeutic arsenal, Khosla said. In addition to patient concerns about rare side effects, the efficacy of most bisphosphonates beyond 5 years is unclear, and a “perfect” long-term, antiresorptive therapy is not yet an option, Khosla said. There is also still a need for new anabolic drugs.
Those limits should serve as an opportunity to develop new agents that lack these complications, he said.
“Even with romosozumab — the best of the anabolics —the anabolic effect lasts about 6 months, and then after 6 months, romosozumab looks like a traditional antiresorptive drug,” Khosla said. “So, we haven’t quite figured out the biology of how to continue to increase bone formation beyond 6 to 9 months.”
A new target: Aging
Khosla noted that chronic aging diseases are typically treated with single drugs for single diseases: statins for cardiovascular risk reduction, antihyperglycemic drugs for diabetes and bisphosphonates for osteoporosis, for example. This, Khosla said, leads to polypharmacy, along with an increased risk for side effects, adverse drug interactions and noncompliance with therapies.
But by targeting a single anti-aging mechanism — cellular senescence, or the lack of cell proliferation — multiple, age-related diseases, including osteoporosis, might be slowed or even prevented, Khosla said.
There is now growing evidence that senescent cells accumulate in tissues with aging, Khosla said. The main tissue dysfunction they cause is through the senescence-associated secretory phenotype, or SASP, which consists of pro-inflammatory cytokines and chemokines.
“These cells have now been shown to accumulate in multiple tissues, and there is an exploding body of literature on this,” Khosla said. “The hypothesis in the gero-science community is that if you target these cells, perhaps you can rejuvenate or prevent some of the aging-related morbidities.”
In aging, there is an accumulation of senescent osteocytes in bone, Khosla said. These cells have a high expression of multiple SASP markers, which could lead to an inhibition of bone formation and an increase in bone resorption, he said.
Data suggest a causal role for senescent cells in bone loss with aging, with a “clearing” of senescent cell burden reducing frailty and increasing the lifespan of mice, Khosla said. In mouse models with old mice (aged approximately 20 months) with established bone loss, 2- to 4-month treatment with either senolytic interventions (clearing the senescent cells to rejuvenate tissue) or senomorphic interventions (inhibiting SASP production) improved bone mass, bone microarchitecture and bone strength in the mice, Khosla said.
The specificity of the interventions to aging was demonstrated in similar research with young mice, where no skeletal effects were observed with the same treatments, Khosla said. Additionally, by eliminating senescent cells or inhibiting SASP, cardiovascular function and insulin sensitivity in mice also improved, Khosla said.
“The holy grail is if you can target this pathway ... perhaps, you can change the time course of an individual’s life, where they have a longer period of a healthy lifespan,” Khosla said. “Maybe a longer lifespan, but at least the time that they have is spent with less frailty and less aging-related comorbidities.”
The research, Khosla said, is moving rapidly. Clinical trials targeting senescent cells are already underway, including a pilot study with cancer patients at Mayo Clinic and a proof-of-concept study using a senolytic drug.
“These studies are rapidly moving from preclinical models to early phase clinical trials,” Khosla said. – by Regina Schaffer
Khosla S. Current and Evolving Approaches for Osteoporosis Management. Presented at: AACE Annual Scientific and Clinical Congress; May 16-20, 2018; Boston.
Disclosure: Khosla reports he has served as an unpaid consultant for Active Life Science and on the scientific advisory board for Surrozen, Inc.