Long-Term Effects of Bisphosphonate Therapy

In a March 6, 2017 Scientific Report article, Dr. Ma (Dept. of Mechanical Engineering, Imperial College, London), et al. presented findings from a study that investigated the effects of bisphosphonate therapy on the microstructure and strength of bone. Dr. Ma looked at three cohorts of individuals from a total of 21 bone samples: 1) eight were from bisphosphonate-treated patients who

had sustained bone fractures, 2) eight were from patients who had sustained bone fractures but who had not received bisphosphonate therapy, and 3) five samples from cadavers of healthy, ageing, non-fracture individuals.

By using X-ray micro-CT and image segmentation technology, the researchers could assess both trabecular microdamage and mechanical strength of the bone samples. What they found was that bisphosphonate therapy is capable of reducing trabecular perforations (A phenomenon that weakens bones when excessive and one which I describe as "disconnected trabeculae" in my book - pages 14 and 15 - The Whole-Body Approach to Osteoporosis.) but causes an accumulation of microcracks. This abundance of microcracks (compared to the cohort that did not receive bisphosphonate therapy) lead to a loss of microstructural integrity and bone strength.

This study explains why short-term bisphosphonate use (2 years or less) can be beneficial (especially in a person with elevated osteoclastic bone resorption that is not being controlled through diet, lifestyle changes, and nutritional supplementation), but that long-term use of these drugs can be detrimental to skeletal health and strength.

The bottom line is that bisphosphonate medications can be of help in reducing immediate fracture risk in the short term but should not be used as the primary long-term treatment for osteoporosis. What SHOULD be used as primary long-term therapy for bone loss is bone-healthy nutrition and exercise, ensuring optimal GI health, and making changes in life style to promote overall health. 

Ma, et al. 2017. Long-term effects of bisphosphonate therapy: perforations, microcracks and mechanical properties.

Scientific Reports DOI: 10.1038/srep43399

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Osteoporosis and Vascular Calcification

In a study published in Climacteric, C.E. Lampropoulos, et al. assessed the correlation between osteoporosis and vascular calcification in postmenopausal women. The goal was to determine not only if there was a correlation (there have been numerous studies linking these as comorbidities) but also to determine if low dose calcium supplementation plus vitamin D contributed to calcification of arteries.

The study concluded that "Calcified plaques were significantly correlated with osteoporosis."  Osteoporotic women were "16 times more likely" to develop calcification of the abdominal aorta and "seven times more likely" to develop plaques and thickening of blood vessels compared to normal individuals. It also concluded that "low doses of supplements do not appear to cause any increase in vascular calcification in osteoporotic women." In other words, although bone loss and calcification of arteries go hand in hand their connection is NOT due to taking calcium supplements. And this is key! We need calcium for our bones to be healthy.

Taking supplemental calcium is safe when used in moderation. Taking huge amounts of any supplement, including calcium, is never advisable. But a sensible intake of 600 to 1,000 mg/day of supplemental calcium (plus another 500 or so from the diet) is important for getting your 1,200 to 1,500 mg calcium/day as recommended by most bone-health experts. Making sure you get adequate vitamins D and K, and magnesium is also a vital part of the equation. You NEED these to ensure that the calcium you take in goes to the right places in your body: muscles, nerves and bone...and NOT settle into the blood vessels!

So what is it that makes women with bone loss be more susceptible to calcification and hardening of the arteries? The answer is INFLAMATION. We at OsteoNaturals know that simply taking in adequate calcium is NOT the total answer to improving bone health. The MOST important thing you can do for better bone health is to reduce inflammation-driven, excessive osteoclastic bone resorption. Inflammation, not a lack of calcium, is usually what fuels excessive bone loss. And that is where OsteoStim comes to the rescue. OsteoNaturals'OsteoStim has ingredients designed to do exactly that: modulate the activity between the osteoclasts and the osteoblasts so that the bone remodeling process comes more into balance. A balanced bone remodeling system is important for the skeleton to renew itself periodically...important for keeping it young, supple, and strong. AND, not only does OsteoStim have ingredients that promote balanced bone remodeling but it also has 200 mg of a very important antioxidant that, yes, you guessed it...helps prevent blood vessel calcification!

And as Lampropoulos, et al. showed in their research, since osteoporotic women are 16 times more likely to develop calcifications it is EXTREMELY important to address this head on! Alpha lipoic acid is THE perfect antioxidant that can help prevent this calcification. Studies such as the one by Ying, et al. demonstrate this beneficial effect. In this 2010  research, published in Life Sciences, Ying, et al. showed that lipoic acid "reduced atherosclerotic plaques in the abdominal aorta".

The combined effect of supplemental calcium, magnesium and other minerals from OsteoSustain and OsteoMineralBoost, plus improved bone remodeling and lowered atherosclerotic risk from our OsteoStim makes OsteoNaturals products your first choice for improved skeletal health.  

Lampropoulos, C.E., et al. 2016. Osteoporosis and vascular calcification in postmenopausal women: a cross-sectional study. Climacteric April 5:1-5.

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Treatment Sequence with Osteoporosis Medications Matters

The effects of medications on bone can be dramatic. Glucocorticoids (e.g. prednisone and dexamethasone) for inflammation, thiazolidinediones (e.g. Avandia and Actos) for type 2 diabetes, and proton pump inhibitors (e.g. Prevacid and Nexium) all can lead to dramatic bone loss. In fact, bone loss can be so profound from drug therapy that it is very important to talk with your doctor about any possible impact on skeletal health when being prescribed a new medication.

Medications specific to osteoporosis treatment can also be very powerful. Many people are aware that drugs for osteoporosis can cause both minor and severe adverse effects. [The most common drugs available for the treatment of osteoporosis are the antiresorptive bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid) and Prolia (denosumab), and the anabolic Forteo (teriparatide - TPTD).] Most of these drugs can even lead to increased risk for fracture when taken for three or more years. But what many people don't realize is that these drugs are so powerful that it REALLY matters WHICH medication your doctor prescribes first. He or she needs to choose the RIGHT medication for the job...the FIRST time. Guessing is not good here. Getting it wrong can lead to life-threatening consequences. Unlike an antibiotic that can be changed if the first one doesn't seem to be working to kill off an infection, antiresorptive osteoporosis medications can limit the effectiveness of the anabolic drug TPTD...so order is everything when selecting which of these drugs to use in each individual case.

When someone has severe bone loss and they have sustained fractures, it is common to put them on a sequential treatment program of TPTD (the only anabolic drug therapy currently available) for two years followed by a course of treatment with an antiresorptive bisphosphonate or denosomab. This sequential drug therapy can have dramatic and positive results for reducing fracture risk when drug therapy is warranted.

But what if a person with osteoporosis were to be treated initially with a bisphosphonate and THEN, due to a lack of response (no improvement in bone mineral density (BMD) to the antiresorptive drug, was then prescribed TPTD? Is this a wise protocol? Can this sequence lead to increased fracture risk? This is exactly what Dr. Felicia Cosman of Helen Hayes Hospital in NY set out to evaluate. The importance of proper drug sequencing is the subject of her recent perspective in this months issue of the Journal of Bone and Mineral Research.

In a perspective reviews study, Dr. Cosman concluded the following:

1) When selecting a treatment protocol for someone with severe bone loss, if no osteoporosis drug therapy has been used before, Dr. Cosman recommends TPTD anabolic therapy first (if appropriate) followed by antiresorptive therapy.

2) She goes on to say,"...our observations clearly highlight that the common practice of providing patients with first-line antiresorptive therapy and then only after patients have an inadequate BMD response and/or an intercurrent fracture to switch to TPTD is not the optimal utilization of anabolic treatment." Dr. Cosman explains that this is extremely important especially when someone sustains a hip fracture. She states that to transition to TPTD after a course of antiresorptive therapy "might in fact lead to a transient loss of strength in cortical sites, including the other hip. This is critically important in patients with a recent fracture where we know the risk of a second imminent fracture is extremely high..."(Hip fractures are a common cause of premature death. Over 50% of people who fracture a hip will die within the year.) For these cases she recommends concurrent treatment with an antiresorptive agent and TPTD instead of sequential therapy. 

Cosman, F., Nieves, JW., and Dempster, DW. 2017. Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res 32(2):198-202.

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Proton Pump Inhibitors Not Only Cause Osteoporosis but a New Study Points to Increased Risk for Stroke

I am continually dismayed at how many of my patients with osteoporosis are taking PPIs. They have
been prescribed proton pump inhibitors by their medical physicians to help reduce stomach acid and treat the symptoms of heart burn or GERD. But PPIs have the nasty side effect of reducing bone density and increasing a person's risk for breaking a bone. With GERD symptoms easily remedied through conservative, non-drug, therapy, I am always left scratching my head wondering WHY!...Why in the world would doctors prescribe PPIs, especially to their patients with osteopenia or osteoporosis. Most cases of GERD respond well to conservative therapy of dietary changes and the use of probiotics and digestive aids to improve gut function. For the majority of people who experience GERD symptoms, they should not have to use PPIs. And, if they do, these medications should be taken in low doses.

Findings from a recent study out of Denmark indicate there is another reason to stay far away from PPIs if possible. Thomas S. Sehested, a medical doctor from the Danish Heart Foundation, showed an "association between use of PPIs and increased risk of first-time ischemic stroke and a positive dose-response relationship between PPI dose and stroke risk." Dr. Sehested's findings are based on the medical histories of 244,679 individuals. Histories were accessed from nationwide Danish registries in this observational study. The investigation looked at 4 different PPI medications and found that stroke risk increased from 33% to 79% depending on the particular drug being taken. Also, the higher the dose, the higher the risk for stroke.

Sehested, T.S., et al. American Heart Association (AHA) 2016 Scientific Sessions. Abstract 18462: Proton Pump Inhibitor Use Increases the Associated Risk of First-Time Ischemic Stroke. A Nationwide Cohort Study. Presented November 15, 2016.

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Zolpidem (Ambien) Increases Fracture Risk In Men and Women with Osteoporosis

People break bones when they fall. In fact, falling is the number one cause of fractures especially in the elderly. It therefore makes sense that people with osteoporosis should avoid taking medications that increase their risk of falling. That is exactly what a recent study published in Osteoporosis International concluded. Park et al. conducted a large (1,092,925 participants) systematic review and meta-analysis and concluded that Zolpidem (Ambien), a medication often prescribed for insomnia, was associated with increased risk for fracture. The study noted that the increased fracture rate was especially pronounced for hip fractures.

This finding makes total sense when you realize that Ambien, a short-acting nonbenzodiazopine hypnotic, can cause ataxia, poor motor control, difficulty maintaining balance, dizziness, and sleepwalking. The last thing a person with fragile bones needs to be doing is dizzily walking around in their sleep . The kicker here is that a 2012 NIH study published in the British Medical Journal concluded that much of Zolpidem's effectiveness is psychological...in other words, a placebo effect. The study concluded that greater caution should be used when prescribing Ambien to individuals at risk for fracture and that "increased attention should be directed at psychological intervention of insomnia".

Park, S.M. et al.  2016. Zolpidem use and risk of fractures: a systematic review and meta-analysis. Osteoporosis International April 22.

Huedo-Medina, T.B. et al. 2012. Effectiveness of non-benzodiazopine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ (Clinical Research ed.) 345:e8343.

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Supplemental Calcium - Concerns Addressed

Two of the most frequently asked questions I field from patients: #1) Are there safety issues with

supplemental calcium...and specifically...is there an increased risk for heart disease from taking calcium in a pill form? And, #2) Do calcium supplements cause kidney stones?

My response to both is, "no". Calcium supplements ARE safe and especially if you make sure your body has enough magnesium, and vitamins D and K. And, no, there is no convincing evidence that calcium supplements cause stones.    

Questions regarding the safety of supplemental calcium arose 7 years ago when a researcher (Bolland, 2008) announced that taking calcium supplements could modestly increase a person's risk for a heart attack. This literally shocked the nutrition and osteoporosis research worlds. But close scrutiny by other researchers (check out my earlier blog on this topic) called into question both the design of this study, as well as the way Bolland interpreted his results. There has been a raging debate and LOTS of misinformation being disseminated ever since. Some professionals say "just get your calcium through food" while others say "taking supplemental calcium is not only perfectly safe but can be very beneficial to your bones".  

With so many people taking calcium to improve their bone health, the Council for Responsible Nutrition (CRN) stepped in last year to take a good look at all the evidence. Their results:

"Although there was no overall indication of a connection between calcium intake and atherosclerotic heart disease or stroke, a few of the cited studies showed a weak but statistically significant positive association of calcium intake and cardiovascular disease, whereas a similar number show the opposite (protective) effects. Because of these mixed results, Heaney and colleagues determined that the findings from available clinical trials and prospective cohort studies indicated that there is no significant effect of calcium supplements on cardiovascular disease (Heaney, et al., 2012)."

The CRN went on to say: "A wide range of clinical and epidemiological studies discussed by the IOM, the EC SCF, the EVM and several published reviews and meta-analysis have shown no adverse effects with calcium intakes of 2,000 mg or less in adults ages 51 years or older. Based on the judgement of the IOM, the calcium UL for persons aged 19 through 50 years should be 2,500 mg, which is the midpoint between the value for individuals ages 51 years and older and the 3,000 mg UL for adolescents. Considering the quite variable calcium intake from foods, dairy products, and fortified foods, CRN agrees with the EVM that a maximum supplement level for adults should be 1,500 mg. Thus, the CRN UL for supplemental calcium is set at 1,500 mg per day for adults."

When I went to the 2013 American Society for Bone and Mineral Research Annual Meeting in Baltimore, Maryland the question over the safety of supplemental calcium was a huge topic. I spoke with several researchers and the answer was always the same. "Supplemental calcium is safe." A sampling:

Douglas Bauer, et al. Dietary and supplemental calcium intake and the risk of mortality in older men: the MrOS study concluded: "...there was no evidence that supplements increased the risk of mortality among those with the highest dietary calcium intake..." and, "...calcium supplements and the combination of high dietary calcium intake and supplement use were not associated with total or cardiovascular mortality."
Joshua Lewis, et al. The cardiovascular safety of calcium supplementation with or without vitamin D in elderly women: A collaborative meta-analysis of published and unpublished trial level evidence from randomized controlled trials concluded: "The data from this meta-analysis does not support the concept that calcium supplementation with or without vitamin D increase the risk of ischemic heart disease or total mortality in elderly women."

I hope this helps clarify the question about the safety of calcium supplements. Our OsteoSustain has 525 mg of calcium in three caplets. That is 175 mg in each caplet. This amount was chosen for a reason during the formulation process of this product. Obtaining adequate calcium is vital for skeletal health but we also know that it is not good to ingest high amounts of calcium all at once. Since it is virtually impossible to obtain adequate calcium and magnesium from one's diet alone, we need to supplement. This is ESPECIALLY true if you are osteoporotic. But we also want to avoid a "spike" in blood calcium levels...a problem that could potentially interfere with normal heart rhythms. This has been shown (although research has not determined if this has any long term detrimental effect) when a person ingests 500 mg or more of calcium all at once.

Our OsteoMineralBoost contains 140 mg calcium in each caplet. Once again, a very manageable amount of calcium for the body to assimilate without causing any excess spike of calcium in the blood. Taking 3 caplets of OsteoSustain throughout the day (not all at once)* and 1 to 2 caplets of OsteoMineralBoost (also spread throughout the day)* gives a person between 665 mg and 805 mg supplemental calcium. With another 600 mg or so of calcium from the diet, this is PERFECT for someone with bone loss. In addition, with OsteoSustain and OsteoMineralBoost you are also getting bioavailable magnesium, vitamins D and K, and trace minerals...all important for utilizing the calcium and helping your body put this vital mineral where it belongs...in your bones.

For the second question: Do calcium supplements cause kidney stones? With literally hundreds of research studies asking this exact question over the past 25 years you would think we would know the answer to this question. But studies have been conflicting. In an attempt to analyze all of this material, Candelas et al. (2012) did a systematic review from three sources to determine the answer. Candelas examined: 1) Medline and Embase from 1991 to 2010. 2) Cochrane Centered register of Controlled Trials up to 2010, and 3) Abstracts from the annual meetings of the American College of Rheumatology and the European League Against Rheumatism from 2008 thru 2010. Candelas' conclusion: "Calcium supplements in the treatment of osteoporosis alone or in combination with another type of treatment does not significantly increase the risk of nephrolithiasis or renal colic."

From both my clinical and personal experience, I know how important it is for people with osteoporosis to consume (and absorb) adequate calcium. This mineral is vital for improving bone health. But so too are vitamins D and K, and trace minerals. When taken on a regular basis, these nutrients will provide a safe and effective approach to improving skeletal health.  

*If you choose to take 3 OsteoSustain and 2 OsteoMineralBoost per day it is difficult to completely spread these 5 caplets out throughout the day by taking them one at a time. Therefore, it would be perfectly fine to take 2 caplets at a time. For example: Breakfast - 2 OsteoSustain, Lunch - 2 OsteoMineralBoost, Dinner - 1 OsteoSustain. (or any other combination you desire)  

Boland, M.J., et al. 2008. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. Feb 2,336(7638):262-6.

Boland M.J. and Reid I.R. 2011. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access data set and meta-analysis. BMJ. 342:d2040.

Hathcock, J.N. 2014. Vitamin and Mineral Safety, 3rd Edition. Council for Responsible Nutrition, pp 104-110.

Candelas, G., et al. 2012. Calcium supplementation and kidney stone risk in osteoporosis: a systematic literature review. Clinical and experimental rheumatology. Nov-Dec., 30(6):954-61.

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Are You Taking Medications That Could Cause Osteoporosis?

Unfortunately, some medications can actually CAUSE disease. In a recent review article published in Therapeutic Advances in Musculoskeletal Diseases, Panday, Gona, and Humphrey discuss common medications that can cause bone loss. The authors emphasize the importance of being aware of this often over-looked, drug-induced, adverse side effect. Why?...Because many doctors (although they know that aging, menopause, and chronic illness can lead to osteoporosis) fail to realize that certain drugs, even ones they may be prescribed to YOU, can also lead to severe bone loss. In other words...be aware of the "adverse effects" linked to any medication that you might be taking.

Commonly prescribed drugs known to cause bone loss and increase fracture risk:  
- glucocorticoids (GC)
- proton pump inhibitors (PPIs)
- selective serotonin receptor  
  inhibitors (SSRIs)
- thiazolidinediones (TZDs)
- anticonvulsants
- medroxyprogesterone acetate
  (MPA)
- hormone deprivation therapy
- calcineurin inhibitors
- chemotherapies
- anticoagulants

You may not realize it but your skeleton is very much alive. Bones are metabolically active and can be adversely affected by foreign chemicals such as the medications you are taking. Medications, although they can be extremely helpful, are foreign to the body and can cause adverse effects such as a loss of bone.

For bones to remain strong and healthy throughout your life they must undergo a constant renewal process called remodeling. At any one time, 5% of your skeleton is being remodeled and over the period of several years your whole skeleton will be completely renewed due to this process. When bone is stressed during normal daily activities it incurs small cracks called microfractures. Over time, if these cracks were not removed and strong new bone put in their place, the bone's microarchitecture would weaken leading to increased fracture risk. To prevent this, special cells called osteoclasts eat away the weakened bone with cracks, then other cells, the osteoblasts, come to the site and form new bone. This remodeling process is vital for continued bone health and is overseen by a third type of bone cell called the osteocyte. The problem with certain medications is that they can interfere with normal osteoclast, osteoblast, and osteocyte activity thus disrupting the remodeling process and causing bone loss.

Glucocorticoids

Of all the drugs that cause bone loss GCs are the most aggressive robber of bone density and structural strength. They are also some of the most widely used medications. Physicians use GCs (almost like candy, unfortunately) to treat autoimmune diseases, inflammation, dermatological and respiratory diseases, malignancies, and organ transplants.

GCs adversely affect bone by altering the activity of all three of the bone cell types (osteoclasts, osteoblasts, and osteocytes). When the cells are disrupted, the remodeling process becomes uncoupled leading to a loss of bone density and microarchitectural integrity. GCs have both direct and indirect effects on bone.

     The direct effects:

       -  prolonged osteoclastic survival time thus more bone area being resorbed than
           the osteoblasts are capable of replacing

       -  limit in the number of osteoblast cells formed, therefore a reduction in new
           bone formation

      -  premature death of osteocyte cells which causes bone fragility even before there
          is a detectible loss of bone mineral density. (This means that people taking GCs
          can be at increased fracture risk even before a bone density (DXA) examination
          shows a loss of mineral density.

     The indirect effects:

       -  decrease in calcium absorption, suppression of growth hormone, altered
           sex hormones, and abnormal release of parathormone.

Fracture risk increases as the daily dose of GCs increases. For example, studies have shown that taking a daily dose of 7.5 mg can increase fracture risk five fold. Taking 10 mg/day for 90 days can lead to a 17-fold increase in fractures. Even the low dose of 2.5 mg prednisone can increase fracture risk.  A major problem with monitoring fracture risk of patients who take GCs is that their risk increases even BEFORE changes in bone mineral density can be detected.

Proton Pump Inhibitors

PPIs cause a moderate increase in fracture risk. While the mechanism by which PPIs increase fracture risk is not fully understood, it is thought that their action in suppressing digestive acids leads to reduced calcium (as well as other nutrients) absorption. Studies indicate that PPI use for as short as one year can increase hip fracture risk 20 to 60% and spine fracture risk 40 to 60%.  Several studies have indicated that patients taking bisphosphonate medications for osteoporosis who also take PPIs are at a further increased risk of fracture.

Antiepileptic drugs

AEDs are not only used to control seizures in epileptic patients but they are also used to treat migraines, psychiatric disorders, chronic pain, and neuropathy. AEDs cause bone loss by interfering with vitamin D and the bodies ability to absorb calcium. They also prevent osteoblast proliferation and the production of osteocalcin, a glue-like compound necessary for strong healthy new bone. The most commonly used AEDs known to increase fracture risk are: carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin.

Medroxyprogesterone acetate

MPA, a contraceptive and medication for the treatment of endometriosis, suppresses estrogen production and can lead to substantial bone loss especially during the first two years of use. Although this bone loss is often reversible when MPA is discontinued, increased fracture risk may remain.

Aromatase Inhibitors

The AIs letrozole, anastrozole, and exemestane are used to treat estrogen-receptor-positive breast cancer in postmenopausal women by reducing estrogen levels. With the production of estrogen falling below normal menopause levels, bone loss occurs even more rapidly. Because of this, all women starting AI therapy should receive a bone density (DXA) examination and be encouraged to obtain adequate calcium and vitamin D intake.

Gonadotropin-releasing hormone agonists and androgen-deprivation therapy

GnRHs for the treatment of polycystic ovary syndromes, endometriosis, uterine myomas, and breast and prostate cancer, and ADT for the treatment of prostate cancer, can lead to bone loss and increased fracture risk. All patients receiving these medications should receive a DXA examination as well as extra calcium and vitamin D supplementation.

Selective serotonin reuptake inhibitors

SSRIs are commonly used medications for the treatment of depression, anxiety disorders, premenstrual syndrome, peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain. Although the exact mechanism for SSRIs adverse effects on bone are not completely understood, studies indicate these medications lead to reduced bone mineral density and increased fracture risk.

Thiazolidinediones

The TZDs rosiglitazone and pioglitazone are used to treat type 2 diabetes mellitus.  TZDs reduce bone density and increase fracture risk by stimulating osteoclast bone resorption, impairing the development of bone-building osteoblast cells, and causing a build-up of fat within bone marrow.

Calcineurin inhibitors

These drugs are used as immunosuppression agents to prevent organ transplant rejection and for the treatment of certain autoimmune disorders. The extent to which this group of medications can contribute to bone loss and fracture risk has not been fully studied.

Anticoagulants

Long-term use of the anticoagulant heparin (used in the treatment of venous thromboembolism) leads to loss of bone mineral density and an increased fracture risk. Although the bone loss associated with heparin is usually reversible, studies indicate substantial bone loss and increased fracture risk can occur within 6 months of starting heparin therapy.  The anticoagulant, warfarin, may also reduce bone density but its full impact on bone health and fracture risk is still under study.


Panday, K., Gona, A., and Humphrey, M.B. 2014. Medication-induced osteoporosis: screening and treatment strategies. Therapeutic Advances in Musculoskeletal Disease 6(5):185-202.

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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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