Thursday, May 2, 2013

Zoledronic Acid: New Research

Medications play an important role in the treatment of chronic diseases, but they need to be used judiciously and wisely. A recent article on zoledronic acid (Reclast and Zometa) -- a bisphosphonate medication used to treat osteoporosis and high blood levels of calcium caused by cancer -- illustrates how a stop-gap method for one diagnosis can have dire consequences for an individual's health in the long run.

We already knew that zoledronic acid dramatically inhibits osteoclasts from destroying bone and this can be a good thing, especially when someone has severe osteoporosis and is at great risk for fracturing. In a study published in the Journal of Clinical Endocrinology and Metabolism, ¹ Catalano et al. from the University of Messina, Italy focused on forty postmenopausal women with osteoporosis, looking at the effects zoledronic acid has on sclerostin, a protein secreted by osteocytes that inhibits Wnt signaling ² in osteoblasts and reduces their ability to form bone. The findings from this study are somewhat alarming: those given zoledronic acid had a dramatic increase (three fold) in sclerostin serum levels for a full year before returning to baseline. To repeat, bone formation stops within several days of beginning treatment and for a full 12 months the bones essentially become dormant. Nothing happens. Bone remodeling is shut down, setting the stage for osteonecrosis ³ of the jaw (ONJ) and bone fragility leading to atypical femur fractures.

What I found most disturbing about this study was the way many researchers (and the pharmaceutical companies) interpreted the results. Instead of questioning the length of time remodeling is shut down and how long bone can survive before it becomes really unhealthy, researchers saw the results of this study as an "opportunity" to investigate a new drug that could be used in combination with zoledronic acid to lower sclerostin levels, increase bone formation and reinstate remodeling. Of course, there no doubt would be adverse effects brought about by anti-sclerostin drugs (there are actually several anti-sclerostin drugs currently in trials) that could again be countered by a third medication.

Zoledronic acid commonly causes flu-like aches and pains, fever, muscle and joint pains, chest pain, bone pain, difficulty breathing, persistent cough, vision problems, headaches, dizziness, anxiety, numbness, hair loss, fatigue, diarrhea, constipation, kidney failure, anemia, nausea, conjunctivitis, atrial fibrillation, high or low blood pressure, rapid heart beat, rash, depression, confusion, urinary tract infections, cancer. An FDA Alert shows that from 11/01/1997 to 8/27/2012, there have been 17,897 reports of a serious adverse event where ZOMETA was identified as the primary suspect drug causing that event; the top three were: osteonecrosis, death and osteonecrosis of the jaw. For Reclast the numbers were somewhat lower at 10,091 reported serious side effects (top 3 adverse events being death, arthralgia and pain). I would hate to see what those numbers would be if we added another drug to the mix. [Note: Zometa is a more concentrated (4 mg/5ml) form of zoledronic acid than Reclast (5 mg/100 ml). Zometa is also infused more often than Reclast. For these reasons the incidence of severe adverse effects is lower for Reclast. That said, similar adverse effects are seen with both drugs but the incidence is proportional to cumulative dosage.]

Every drug has its adverse effects. That isn't to say we shouldn't use medications, but we must also recognize that the body's physiology is extremely complex. Natural repair and regenerative measures to positively influence whole-body health should be first and foremost in our therapeutic arsenal. In the case of osteoporosis, let's  try and encourage anabolic mechanisms that naturally promote healthy bone remodeling. Relying on a medication or a combination of medications to return our skeleton back to health probably won't succeed.


¹ Catalano, A. et al. 2013. Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis. J Clin Endo Metab April 17 [Epub ahead of print].

² The Wnt signaling pathway is a network of proteins that passes signals from receptors on the surface of the cell through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of target genes.

³ Osteonecrosis is the loss of blood supply to bones -- causing bone tissue to die.






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