Risk of Osteonecrosis from Bisphophonates

Key takeaways:
~ A small percentage of people taking bisphosphonates will experience osteonecrosis – bone death – in the jaw.
~ A number of factors are involved in who is at risk, including genetics. Your doctor can help with evaluating your personal risk.
~ A polygenic risk score involving 5 osteoporosis-related genes can show the genetic component of your risk.

How do bisphosphonates work?

Bisphosphonates are a class of medications primarily used to treat osteoporosis and other bone diseases, such as multiple myeloma, that involve excessive bone loss or abnormal bone remodeling. They are also used in some metastatic cancers.[ref]

Bisphosphonates work by inhibiting the activity of osteoclasts, which are the cells that break down bone tissue.  They attach to hydroxyapatite crystals in bone and interfere with the activity of osteoclasts. This prevents them from breaking down bone, leading to increased bone density and a reduced risk of fractures. 

Osteonecrosis – death of the bone tissue – was first noted in the jawbone as a side effect of bisphosphonates in cancer patients in 2003. This can then require surgery to remove part of the jawbone. It is a problem with both the first and second-generation bisphosphonate drugs.[ref][ref][ref][ref]

Not everyone gets osteonecrosis with bisphosphonate use. For many people, the drugs can improve bone strength.

A study by the University of Florida in 2011 looked at genetic variants that were likely to play a role in jaw osteonecrosis from bisphosphonates. The study was small (78 participants), but the researchers were able to discover a statistically significant set of genetic variants related to an increased risk of bisphosphonate-induced osteonecrosis of the jaw. They found that a polygenic risk score of >5 was associated with a significantly increased risk of osteonecrosis.[ref]

A polygenic risk score combines the effects of common genetic variants — adding up the small risks to see if the combination of variants increases the odds of a condition occurring.

Lifehacks:

Again, please talk with your doctor to determine what course of action is best for your situation. Genetics is only one variable involved in the decision.

Lifestyle and environmental factors that influence osteoporosis risk that you can control include:

• cutting back on alcohol
• never smoking
• get enough calcium in your diet
• exercise regularly
• get vitamin D through supplements or sunshine
• eating a healthy diet that promotes a healthy gut microbiome[ref]

Natural RANKL Inhibitors

RANKL inhibitors are a new class of osteoporosis medications, but they come with side effects that may prevent them for being a good fit for some people. There are several natural options for RANKL inhibitors. Keep in mind that TNFSF11 is the gene that encodes RANKL.

• Fermented oyster extract:
  One natural RANKL inhibitor is a fermented oyster extract. It helps to scavenge excess reactive oxygen species that induce RANKL.[ref]
• Ginkgo biloba:
  An extract from Ginkgo biloba inhibits RANKL.[ref] In addition, another study showed that Ginkgo biloba improved osteogenic differentiation of stem cells (bone formation).[ref]
• Hesperetin (hesperidin):
  Hesperidin is a flavonoid found in citrus fruits. It has been shown in animal studies to inhibit RANKL.[ref] You can buy hesperetin as a supplement online or find it at your local health food store. Related article: Hesperidin research studies

Vitamin K: MK-4
A recent meta-analysis of 36 randomized controlled trials found that the overall fracture rate for osteoporosis patients was reduced when they took vitamin K. The bone mineral density was also higher in patients who were supplemented with vitamin K.[ref]

How much vitamin K and what type? A dose-response trial of the MK-4 form of vitamin K2 found that there were increasing benefits at 5 mg/day, but that upping the dose to 45mg/day didn’t give an added benefit.[ref]

Related article: Vitamin K Genes

Maresins and pro-resolving mediators:
The resolution of inflammation is an active process, and increased inflammation is involved in osteoporosis. DHA is the building block for maresins, and it is found in fish oil, krill oil, and algae oil.  If you don’t get enough DHA in your diet, you could consider supplementing with high-quality marine oil. [ref][ref]

Related article: Specialized pro-resolving mediators

Vitamin D supplementation, only if deficient:
A meta-analysis that combined the data from several large randomized controlled trials found that supplemental vitamin D plus calcium reduced fractures by 15% overall and by 30% for hip fractures.[ref] Another clinical trial found that resveratrol – especially when stacked with vitamin D – helped to reduce T scores.[ref]

Calcium plus vitamin D: Take before bed
A study of women in Ireland with osteopenia investigated whether the timing mattered for supplementing with a milk-based protein supplement. The results showed that drinking the milk-based protein supplement (with calcium and vitamin D added) before bed reduced the breakdown of bone overnight. The whole study is available as an open-access study, so you can read it for yourself.

Melatonin Supplementation:
A 2025 clinical trial found that 12 months of 20 mg/day of melatonin supplementation improved bone mineral density in patients with Thalassemia. [ref]

Avoiding Proton Pump Inhibitors (PPIs): 
There is a possible link between increased fracture risk and the use of PPIs. If you have an increased osteoporosis risk due to your genetic variants, talk with your doctor if you are on a PPI about your risk and alternatives.[ref]

Recap of your genes:

Related articles:

Osteoporosis: Genetic Susceptibility and Prevention Strategies