Red sage, otherwise known as danshen, is a key herb in traditional Chinese medicine. Used to treat a wide range of complaints, ranging from cardiovascular issues to renal failure, the herb remains in common use as a complementary remedy.
It would be easy, of course, to dismiss the purported benefits as a collection of old wives’ tales – and certainly, the clinical evidence base remains patchy. However, researchers at the University of British Columbia (UBC) have found that red sage may indeed have some clinical utility. Specifically, they believe a compound derived from the herb could form the basis of a new osteoporosis drug.
According to Dieter Brömme, a professor in the faculty of dentistry, this compound can selectively block an enzyme called Cathepsin K (CatK), which plays an important role in bone collagen breakdown.
“The pharma industry has recognised for a long time that Cathepsin K is a good target for treating osteoporosis,” he says. “They have been trying to develop Cathepsin K inhibitors since 1996.”
It’s an area Brömme knows well, having been one of the original discoverers of CatK in humans. As he explains, its early promise as a therapeutic target has fallen frustratingly short – while a number of pharma companies have tried to develop drugs of this nature, none have successfully completed clinical trials.
“Four companies – Merck, Novartis, Ono Pharmaceutical and Medivir – developed very specific, potent Cathepsin K inhibitors, and went into various stages of clinical trials,” he says. “Novartis decided to eliminate that project because there was a substantial risk of skin fibrosis. Merck officially quit their project in 2016 due to the increased risk of stroke. Ono’s drug seemed to have a side effect with skin issues. And to my knowledge, Medivir’s osteoporosis trial was cancelled with no explanation.”
All these compounds, he says, appeared to work very well as anti-osteoporosis drugs, but had problems when it came to side effects. He believes the compound in red sage could be just as effective, albeit without the risks.
Targeting the mechanism
The need for such a drug is not in doubt. Osteoporosis, a disease resulting in loss of bone, affects around 10% of the population in Europe, Japan, and North America, and its prevalence is likely to grow as the population ages.
Currently, it is managed by treatments such as hormone replacement therapy (HRT) or bisphosphonates, along with lifestyle changes. However, these options are less than ideal – HRT can increase the risk of breast cancer, heart attack or strokes, while bisphosphonates occasionally lead to debilitating side effects.
Unlike the options currently available, a CatK inhibitor would target the actual mechanism at play. In osteoporosis, there is an imbalance between bone resorption (mediated by a type of bone cell called osteoclasts) and bone rebuilding (mediated by a different kind of bone cell, osteoblasts). Since the CatK enzyme is expressed predominantly in osteoclasts, blocking its activity would prevent excessive bone resorption.
Unfortunately, there has been a problem with the drugs trialled to date, namely that these were ‘active site-directed inhibitors’, which worked by locking the entire enzyme. This meant shutting off both the desired mechanism (collagen degradation), and other functions that are necessary in the body.
“CatK is a multifunctional enzyme, so it plays a role in different organs – it’s everywhere more or less,” says Preety Panwar, a research associate in Brömme’s lab. “It’s in the heart, in the lungs, in the bone. Our aim was to figure out an inhibitor that would block the bone degradation, without affecting the degradation of anything else.”
Screening red sage
The researchers began their work in this field by screening a wide range of compounds, including some from red sage.
“There’s a long history in traditional Chinese medicine of using herbal extracts in bone disease and osteoporosis,” says Brömme. “One of the herbs that was of particular interest, red sage, seemed to be particularly rich in compounds inhibiting the collagenase activity of CatK.”
Ultimately, they selected a compound called Tanshinone IIA sulfonic sodium (T06), which seemed like the best fit for their purposes. After testing it out in human and mouse bone cells, they conducted an in vivo study in mice.
Their results, published in the Journal of Bone and Mineral Research, were striking – mice treated with T06 increased their osteoblast numbers by around 28% compared to controls, and showed a 35% increase in bone mineral density. On top of that, they didn’t suffer any side effects.
“Just to get this in perspective, this compound is only four times less effective than the best CatK inhibitor developed by Merck, which went to a phase 3 trial, and this is without any optimisation,” says Brömme.
Another drug approach
The researchers believe that T06 is a ‘selective antiresorptive CatK inhibitor’. In other words, rather than shutting down the enzyme completely, the compound only locks its collagen degrading activity, leaving its functions elsewhere in the body unaffected.
“The majority, maybe 95%, of enzyme-targeted drugs are active site-directed inhibitors, leading to the total inactivation of the enzyme,” says Brömme. “In this case, it’s good to inhibit the collagenase activity but maybe not so good to inhibit any of its other activities. We already have preliminary data suggesting we can prevent the kinds of side effects that are typically seen with an active side directed inhibitor, so we strongly believe that this approach is a viable alternative.”
While he concedes that the compound may have side effects we don’t know about yet, the early signs certainly seem promising. Brömme believes it could one day provide the basis for a potent anti-osteoporosis drug, with further implications for other bone and cartilage diseases.
“Of course, our dream is to develop this type of compound into another drug approach,” he says.
He points out, however, that it’s still early days. Only further research will tell whether the compound’s apparent potential stands to be realised.
“We’re a small academic lab so what we are doing currently is to get proprietary compounds that will be protected by patent applications,” he says. “It’s hard to convince anybody to use a natural product because they have no commercial protection. We aim to continue with preclinical work, and then hopefully attract major funding from the industry for clinical research.”