Osteoporosis is a complex disease of aging.  Complex means it isn’t caused by “A” but rather it is by “A”, “B”, “C” and “D”.  To further complicate this, one patient may have the disease caused by 20% A, 70% C and 10% D while in another patient, it is caused by 60% A, 30% B and 10% D.  This pattern of “why” having a different answer in different patients creates variability in treatment responses.

To this point, our understanding of the causative factors that drive osteoporosis include:

1. Genetics
2. Lifestyle
3. Hormonal dynamics
4. Cell senescence

Genetic mediated risk osteoporosis is perhaps the risk factor that is least understood and creates the most significant variation in treatment response.  Telling of this variation in treatment response is approximately one third of patients will not respond to the standard drug therapies. (1) The drug class on the left of the diagram, bisphosphonates such as Fosamax, do not improve bone density in 32.2% of users.

The lifestyle/osteoporosis connection involves several factors including diet, exercise and habits such as smoking.  Those are more easily understood and modifiable.  Inflammation drives bone density loss.  There is extensive study on the relationship between diet, exercise and inflammation.  Basically, poor diet and lack of significant exercise drive inflammation and BMD loss.

Hormonal dynamics are a well understood cause of BMD loss.  Estrogen helps maintain the balance in the cells that remove old bone and the cells that replace it with new bone during each remodeling cycle where bone replaces itself.  Declining estrogen triggers an increase in bone removal and a decrease in bone replacement.  The net effect is an approximate loss of 1-3% of BMD each year after the age of 35 and this accelerates to 3-5% after menopause.  Earlier declines in estrogen equate to greater BMD loss at a given age.

Perhaps the newest understanding in the cause of osteoporosis is the role of cell senescence.  Cells such as mesenchymal stem cells (MCSs) that must replace the osteoblasts with each remodeling cycle, get less able to do so each decade.  The net effects are while bone removal is increasing, bone replacement declines.  The math is straight forward; if more bone is lost than is replaced each remodeling cycle, bone density must decline.

So, what is cell senescence?  All cells have the ability to replace themselves with new ones.  This is how tissues constantly repair.  Cells, however, have a limit as to how many times they can do so.  This limit is known as the Hayflick limit where cells lose the ability to replicate after 40 – 60 cycles.  Once they can no longer reproduce, they are termed “senescent”.

Cell senescence has profound effects on our pace of aging and the pace of age-related diseases such as osteoporosis.  As cells become senescent, they should undergo “apoptosis” or cell death.  If this mechanism fails, senescent cells produce large amounts of inflammatory cytokines triggering more bone loss each remodeling cycle and injuring the neighboring healthy cells triggering their senescence.

As the role of cell senescence became understood in the driving of age-related diseases, considerable research is being done on trying to reduce it.  Reducing the rate of senescent cell driven tissue aging is called “senolytic therapy”, senolytic referring to lysing or killing these harmful cells.  Removing these cells prevents their inflammatory injuring of neighboring cells, allowing them to proceed with ongoing tissue repair.

Early senolytic therapy studies used a cancer drug dasatinib. Many cancer drugs are designed to stop cancer cell spreading by making the cells senescent, so they do not reproduce more cancer cells.  As mentioned above senescent cells should undergo apoptosis or cell death and the drug was thought to increase this process.  While dasatinib is senolytic, effective in causing senescent cells to die, it unfortunately causes a lot of side effects from injuring healthy cells.

Eventually, it was discovered that adding the flavonoid quercetin to dasatinib helped it to be more effective in eliminating senescent cells without harming any healthy cells.  As a natural extension of this, the question arose; if a natural food-based flavonoid like quercetin can function as a senolytic helping the natural elimination of senescent cells, could there be other flavonoids to pair with it to help the process?  The answer was a resounding yes.

Fisetin is found in foods such as strawberries, apples and onions.  While these foods can help slow cell senescence, higher doses are needed once age related disease is present. 

As is the case with phytonutrients such as flavonoids, the amount needed to treat many problems can be found in greater amounts in herbs.  The most potent source of fisetin is the herb smoke tree.  Adding quercetin to fisetin enhances the senolytic effect.

Cell senescence is an important driver of bone loss with age.  Fortunately, we now have safe nutritional therapy to correct this mechanism that drives osteoporosis.

1. Jang et al. One-year bone mineral density gains with anti-osteoporotic medications and clinical factors associated with non-BMD gainers. J Bone Miner Metab (2025).
2. Yousefzadeh et al.  Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018; 36:18–28.