Medical / Osteoporosis / March 23, 2012

Denosumab (aka Prolia, Xgeva) – Even Worse than the Bisphosphonates?

Like the bisphosphonates, denosumab (trade names Prolia, Xgeva)(1) also prevents osteoclasts from removing old, damaged or worn out bone. It just does so via a different action than the bisphosphonates — an action that may turn out to have even more harmful side-effects. Instead of poisoning already mature osteoclasts (which is what the bisphosphonates do), denosumab prevents the precursor cells for osteoclasts from ever developing into osteoclasts.

Mechanism of Action — How Denosumab Works

Denosumab (Prolia, Xgeva) does this by binding to and thus blocking off the RANK ligand (RANKL). RANKL is a protein whose job is to bind to a cell receptor called RANK that is found on several different cell types, just one of which is osteoclast precursor cells.  RANK (an acronym that stands for “receptor activator of nuclear factor-kappa B”) is activated by the RANK-Ligand (RANKL). RANK is produced by osteoblasts (yes, osteoblasts — these bone building cells work in concert with osteoclasts to continuously replace old or damaged bone with new bone). When RANKL activates the RANK receptor on the precursor cells for osteoclasts, this signals these osteoclast- wannabes to develop into mature osteoclasts ready to remove worn out bone. By preventing RANKL from doing its job, denosumab (Prolia, Xgeva) prevents osteoclasts from ever maturing and doing theirs.

What problems might arise?

Since denosumab, like the bisphosphonates, prevents normal bone remodeling, one would expect the denosumab twins, Prolia and Xgeva, to produce similar adverse effects, and they do. Far fewer studies tracking outcomes are available in comparison to the bisphosphonates because denosumab just got FDA approval as Prolia in June 2010, and as Xgeva in November 2010. But, already denosumab has been found to cause osteonecrosis of the jaw. Given the hundreds of studies which have now confirmed that, by preventing normal bone remodeling, the bisphosphonates cause not only ONJ, but “atypical” femur fractures, one wonders why the pharmaceutical companies are now attempting to sell us yet another drug that prevents osteoclast function.

Denosumab’s most common side effects, noted to date, include infections of the urinary and respiratory tract, cataract, constipation, rashes and joint pain. A small study has also already found slightly increased risk of cancer and severe infections.  Another trial showed significantly increased rates of eczema and skin infections so severe they required hospitalization.

Why might denosumab increase risk of severe infection or cancer? Well, guess what else must bind to RANKL in order to develop – T and B cells, key cells of our immune system! Obviously, the potential adverse ramifications of this fact of human physiology were somehow overlooked when FDA gave denosumab its stamp of approval.

Osteoclasts and Our Immune System – Tight Buddies

Recent papers have begun to discuss “The tight relationship between osteoclasts and the immune system.” A new interdisciplinary research field called “osteoimmunology” is just beginning to look the interplay between our bones and the immune system. Already, however, a substantial body of evidence is showing that our bones and immune system are connected by two-way regulatory mechanisms that bring them into much closer association to each other “than one could ever predict,” —  to quote a review paper published January 2012.(2)  Well, I’m predicting that by causing osteoclast genocide, denosumab is going to produce some extremely unhappy, “unexpected” (but should have been!) results.

Osteoclasts are strongly linked to our immune system because they belong to the monocyte/macrophage family (these are the white blood cells of our innate immune system), have tight relationships with B and T cells (the adaptive immune system’s fighter squadrons), and differentiate (develop into mature osteoclasts) in response to RANKL, which is also produced by lymphocytes and—here’s the real stinger — RANKL regulates lymphopoiesis!

What’s lymphopoiesis, and why should I care?

Lymphopoiesis is the generation of a broad class of immune cells called lymphocytes, which include natural killer cells, T cells and B cells. And we (all of us, including the pharmaceutical companies) should care because lymphopoiesis is absolutely necessary for life.

Mature lymphocytes are cells that are a critical part of our immune system, and (except for memory B and T cells which are slightly longer-lived), our immune defender cells have very short lives (just days or weeks) and must be continuously generated. Were this generation to stop, the body would be largely undefended from infection. And how are these immune cells generated? By RANKL’s binding to cell receptors on their precursor cells. And what does denosumab do? It binds to and uses up all available RANKL.

Both pre-osteoclasts and immune cell precursors share the requirement of activation by RANKL, which allows them to develop into mature, active cells. Because osteoclasts share this need for RANKL activation with our immune cells, it has recently been hypothesized that osteoclasts are actually immune cells themselves.

Back in 2009, before its FDA approval, a red flag was raised about denosumab’s across the board shut down of RANKL in an editorial in the New England Journal of Medicine: “Perhaps the major concern about long-term use of denosumab relates to its possible effects on the immune system, since RANKL is expressed not just on bone cells but also on immune cells.”(3)

Denosumab’s already seen adverse effects

It seems we don’t have to wait “long-term.” After just a few years since denosumab’s FDA approval, side effects already being seen that certainly suggest its effects on immunity are an issue! Compared to placebo, denosumab has produced significant increases in rates of eczema and hospitalizations for cellulitis, which is inflammation of connective tissue either localized or spread throughout the body along with severe inflammation of the dermis (the layer of the skin immediately below the skin’s surface or epidermis) and its subcutaneous layers (which consist of connective tissue). In a study involving 314 postmenopausal women with low bone mineral density who were treated with denosumab, neoplasms (cancers) developed in 6 patients and serious infections in 3, whereas none of the 46 patients in the placebo group had such complications.(4)

As Amgen, the drug company that developed and holds the patent on denosumab, has noted, the drug produces the same adverse effects as the bisphosphonates:(5)  “Overall rates of adverse events and serious adverse events were generally similar between the two drugs.” Here Amgen is referring to denosumab (Prolia / Xgeva) and zoledronic acid (this is the bisphosphonate marketed under the trade names Zometa, Reclast, and Aclasta). Common side effects for zoledronic acid (and denosumab) include osteonecrosis of the jaw, back pain, pain in the extremities, musculoskeletal pain, high cholesterol levels, and urinary bladder infections.

Of major concern is that far fewer studies have been done using denosumab than the bisphosphonates. As mentioned above, denosumab was only approved by the FDA for use in postmenopausal women with risk of osteoporosis under the trade name Prolia in June 2010, and for prevention of “skeletal-related events” in patients with bone metastases from solid tumors under the trade name Xgeva in November 2010. The point being that we only have short term results as of yet. Denosumab, however, may have much nastier outcomes in store for us than the bisphosphonates because, by binding to RANKL, this drug interferes with our production of immune cells.

A recent review (Bridgeman et al.) of what research has been done on Prolia for reduction of bone loss in postmenopausal osteoporosis (from 1995 – 2011) summarizes a long list of adverse effects associated with the drug:(6)

  • After 24 months, compared with placebo, denosumab was associated with significantly greater prevalences of urinary tract infection and hypertension.
  • After 12, 24, and 48 months, the most commonly reported adverse effects with denosumab use included upper respiratory tract infection, arthralgias, back pain, and nasopharyngitis.
  • Infections requiring hospitalization were reported in denosumab-treated patients (10/314 [3.2%]) but not in patients given alendronate (Fosamax) or placebo.
  • Prevalence of malignant neoplasms (cancer) were higher in the denosumab than in the Fosamax (alendronate) or placebo groups (4.8%, 4.3%, and 4.3%, respectively), as was the overall prevalence of serious adverse events after 48 months of treatment (17.8% for denosumab, 17.4% for Fosamax, and 10.9% for placebo).
  • A greater number of patients developed infections that required hospitalization in the denosumab group compared with placebo (8 vs 1). For some reason, for which no justification or explanation is given, “Infections were not considered to be related to denosumab.”The types of infections included pneumonia, urinary tract infection, pyelonephritis, diverticulitis, appendicitis, sepsis, and cellulitis.
  • Four patients in the denosumab group were reported to have neoplasms compared with 1 patient in the placebo group, but again for some reason for which, again, no explanation is given, the higher incidence of cancer in those given denosumab is said to not be related to the drug.
  • Other adverse events reported at significantly greater rates with denosumab compared with placebo included constipation (11.0% vs 4.8%), sore throat (9.1% vs 3.0%), and rash (8.5% vs 3.0%)

If all this weren’t sufficient cause for concern, Bridgeman et al. go on to also warn that drug-drug interactions may be a serious problem with denosumab:

“Studies of the potential for denosumab to affect the metabolism of other pharmacologic agents were not identified in the literature search. [Translation– no studies looking into this have been conducted]. However, based on reports of serious infections associated with the use of denosumab, the concurrent use of immunosuppressants, including corticosteroids, chemotherapeutic agents, and immune modulators, may increase the risk for infection.” (Many drugs fall under these classifications including drugs prescribed for allergies, asthma, depression, epilepsy, insomnia – our blog “Prescription Drugs that Cause Osteoporosis: Here’s What You Can Do to Protect Yourself” discusses a number of these drugs, which are also known to promote osteoporosis.) (Make the title of the blog a link to it?)

Elsewhere we are simply told that data regarding interactions between denosumab and other drugs are “missing.” (Translation – they haven’t looked into this.) But we are assured such interactions are “rare,” so “it is unlikely that denosumab exhibits any clinically relevant interactions.” (Translation – we haven’t seen this yet, so are not going to worry about it until enough people have been harmed that a class action suit is brought.) (7)

The following quote from the concluding section of Bridgeman et al’s review of the research on denosumab use in postmenopausal women at risk of osteoporosis summarizes the adverse events already seen:

“Adverse events reported with the use of denosumab have included back pain (34.7%); pain in the extremities (11.7%); general musculoskeletal pain (7.6%); elevated cholesterol (7.2%); inflammation of the bladder (5.9%); and dermatologic conditions including dermatitis, eczema, and rashes (combined prevalence, 10.8%). Serious adverse events have included hypocalcemia (1.7%), pancreatitis (0.2%), and severe infection (0.2%). Several cases of osteonecrosis of the jaw have also been reported.”

Shockingly, the next sentence, the concluding statement of this review, is: “Based on the data from the available literature, denosumab is an efficacious and well-tolerated treatment for postmenopausal osteoporosis.” This was such a non-sequitur to me, I read the paragraph several times trying to make sense of it – I couldn’t.

Denosumab has little benefit, nasty side effects in men with prostate cancer

Most recently, Amgen has attempted to have denosumab as Xgeva also approved to increase bone mass in men with non-metastatic prostate cancer who are at high risk for fracture because they are being given “androgen deprivation therapy” (drugs that shut off men’s production of testosterone). Remember, in men, a little testosterone is converted into estrogen that plays a very important role in building men’s bones. Drugs that prevent a man from producing testosterone therefore also cause him to lose bone.

Amgen approached FDA for approval using data from its study of 1,432 men with non-metastatic, castration-resistant prostate cancer. These men were randomly assigned to receive calcium and vitamin D supplements plus either 120 mg subcutaneous denosumab every four weeks or placebo. (Dosing for denosumab is a 60 mg subcutaneous injection every six months for postmenopausal osteoporosis and 120 mg every 4 weeks for patients with solid tumors.)

Men in this study who were given denosumab did have, on average, about four months longer before developing bone metastases compared to those in the placebo group (29.5 months versus 25.2 months), but the men’s overall survival and cancer progression-free survival were not any better in the denosumab group versus placebo. Nor did denosumab lessen the men’s pain or improve their health-related quality of life compared to placebo.

As expected from prior studies, denosumab did, however, cause a number of adverse effects in these men, including more hypocalcemia (1.7% versus 0.3% with placebo) as well as a 5% rate of osteonecrosis of the jaw, which didn’t occur at all in the control group. Just think about this – it’s bad enough having prostate cancer and suffering the effects of having your testosterone wiped out, but to also have to endure a rotting jaw is completely unacceptable!

FDA reviewers concerned about “unresolved safety issue”: might denosumab cause cancer?

FDA reviewers were also concerned about an “unresolved safety issue”: whether denosumab might cause cancer to spread to non-bony sites. Why is the FDA concerned? Remember denosumab works by shutting down RANKL, which is required for the activation of our T and B immune cells. In just living our lives, normal bodily metabolism and environmental exposures result in each of us experiencing insults to our cells’ DNA that produce hundreds of potentially cancerous cells every day; our immune system, if not overloaded and not prevented from functioning properly, destroys them.

Amgen argued that denosumab should be approved for the added indication anyway “because no other therapy has been shown to prevent the development of bone metastases in patients with non-metastatic castrate-resistant prostate cancer.” Am I missing something in the logic chain here? Denosumab should be approved–not because it has been shown to help prevent bone cancer in men with non-metastatic prostate cancer or extend their lives or even improve the quality of whatever time they have—but because no other drug has been shown to do so? (8)

Denosumab – another pharmaceutical company experiment — on us!

Even for its use only to prevent excessive bone loss in individuals with osteoporosis, denosumab has only received approval by the FDA as of 2010. As two recent papers in leading medical journals focusing on osteoporosis clearly warn, bone remodeling continues throughout the human lifetime, so any treatment used to prevent excessive bone loss must be safe over many years – for which reason, “the collection of long-term efficacy and safety data [on denosumab] is warranted.”(9) “Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed.”(10)

Despite these concerns voiced in leading medical journals and by the FDA, the fact that denosumab has already been found to produce adverse effects, and its far less than stellar results in men with non-metastatic castrate-resistant prostate cancer, a Wall Street Journal post entitled, “Analysts React to FDA Panel: ‘It Wasn’t a Perfect Day for Amgen,” noted that annual worldwide sales of denosumab are still projected to reach $5 billion by the year 2015. (11) Well, at least Amgen should have plenty of money available for the lawsuits sure to come when denosumab’s impact on bone and immune health has resulted in serious harm to sufficient people. Don’t be one of them!

Haven’t the atypical fractures and osteonecrosis of the jaw caused by the bisphosphonates provided a clear enough warning? Why would we want to expose ourselves to yet another drug that shuts off osteoclasts and prevents the normal levels of bone remodeling essential for healthy bones? And denosumab’s undesirable long term effects could be much, much worse because this drug not only prevents osteoclasts from developing, but does so by locking up RankL, which key cells of our immune system, our T and B cells, also require in order to develop.

Latest research proves you can restore the health of your bones—safely and effectively — naturally

Why participate in yet another pharmaceutical company experiment and expose yourself to these risks when the latest research proves you can maintain and restore the health of your bones – safely and effectively — naturally?

Just last month (February 2012), right after the annual meeting of the American Academy of Orthopaedic Surgeons officially warned doctors that the bisphosphonates increase risk for “atypical femur fractures,”(12) the results of the one-year long Combination of Micronutrients for Bone (COMB) Study were published in the prestigious Journal of Environmental and Public Health. The COMB study unequivocally demonstrated that providing our bones with the nutrients they need along with regular weight-bearing exercise is as or more effective than any of the bisphosphonates or strontium ranelate (the unnatural drug version of strontium). And a lot less expensive!

What was the protocol utilized in the COMB Study?  Daily vitamin D3 (2,000 IU), DHA (250 mg), K2 (in the form of MK-7,100 mcg), strontium citrate (680 mg), magnesium (25 mg), and dietary calcium. In addition, daily impact exercise was encouraged.(13)

As one of the lead researchers, aptly named Dr. Stephen Genius, noted, not only was this combination of nutrients that bones require “at least as effective as bisphosphonates or strontium ranelate in raising BMD levels in hip, spine, and femoral neck sites,” but the nutrient supplement regimen was also effective “in individuals where bisphosphonate therapy was previously unsuccessful in maintaining or raising BMD.”

What a concept – by providing our bodies with the nutrients our bones require and enjoying a little weight-bearing exercise, we can build strong bones for life, safely, effectively – naturally!  If you are taking AlgaeCal Plus and Strontium Boost, you’ll more than match the nutrient levels provided in the COMB study. All you need to add to your bone building program to mimic the COMB recommendations is some daily, weight-bearing exercise.

The COMB study’s recommendation for daily weight-bearing exercise is based on earlier studies in which regular exercise improved women’s bone density.(14), (15)The most recent of these studies, Niu K et al. 2010,  is especially encouraging since it showed that even 3 short exercise sessions each week can have a beneficial effect on bone density. This study used a video-guided exercise program, which premenopausal women in Japan were asked to participate in during short breaks at work at least three times a week.

Each exercise session included a 3-minute warm-up (stretching), followed by 10 additional minutes of stretching and balance exercises or some “high intensity” exercises (this routine also began with stretching, then added some jumping, and after 6 months, stair-stepping, followed by a 3 minute cool down of more stretching). The women in the high intensity program started out with as few as 5 jumps. Programs were modified monthly by increasing the number of jumps up to 50 jumps during the first 3 months. After 6 months, stepping up and down using a 10-centimeter step bench was also added. Both the stretching and “high intensity” exercise sessions were done with the accompaniment of music and supervised at least 4 times a month by an experienced health fitness instructor. Both exercise programs – stretching and “high intensity” — were beneficial, but women the stretching program maintained their BMD, while those in the “high impact” program increased theirs, both in the spine and neck of the femur.

The “take home” message here: just a few daily minutes of energetic exercise – exercise that puts enough load on your bones to send them a clear “get buff” message — can really help your bones! Combine exercise with a healthy dose of the nutrients your bones require to build, and you’ll have strong, healthy bones for life – naturally.


  1. ^Prolia is the trade name given to denosumab marketed to women at risk of osteoporosis; Xgeva is the trade name given to the drug when used for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
  2. ^Fattore AD, Teti A. The tight relationship between osteoclasts and the immune system. Inflamm Allergy Drug Targets. 2012 Jan 20. [Epub ahead of print] PMID: 22280239
  3. ^Khosla S. Increasing options for the treatment of osteoporosis. N Engl J Med. 2009 Aug 20;361(8):818-20.PMID: 19671654
  4. ^McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821-831. PMID: 16495394
  5. ^
  6. ^Bridgeman MB, Pathak R. Denosumab for the reduction of bone loss in postmenopausal osteoporosis: a review. Clin Ther. 2011 Nov;33(11):1547-59. PMID: 22108301
  7. ^Haberfeld, H, ed. (2009) (in German). Austria-Codex (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  8. ^Walker, Emily P. (February 7, 2012). “Benefit of Bone Drug in Prostate Cancer in Doubt“. MedPage Today.
  9. ^Dore RK. Data from extension trials: denosumab and zoledronic Acid. Curr Osteoporos Rep. 2012 Mar;10(1):16-21. PMID: 22086442
  10. ^Body JJ, Bergmann P, Boonen S, et al. Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications. Osteoporos Int. 2012 Feb;23 Suppl 1:S1-23. Epub 2012 Feb 4. PMID: 22311111
  11. ^
  12. ^Am Acad Orthopaedic Surgeons 2012 Mtg: Abstract 190, presented 2-8-12):
  13. ^Genuis SJ, Bouchard TP. Combination of Micronutrients for Bone (COMB) Study: bone density after micronutrient intervention. J Environ Public Health. 2012;2012:354151 PMID: 22291722
  14. ^Korpelainen R, Keinänen-Kiukaanniemi S, Heikkinen J, et al. Effect of impact exercise on bone mineral density in elderly women with low BMD: a population-based randomized controlled 30-month intervention. Osteoporos Int. 2006 Jan;17(1):109-18. Epub 2005 May 12. PMID: 15889312
  15. ^Niu K, Ahola R, Guo H, et al. Effect of office-based brief high-impact exercise on bone mineral density in healthy premenopausal women: the Sendai Bone Health Concept Study. J Bone Miner Metab. 2010 Sep;28(5):568-77. Epub 2010 Mar 30. PMID: 20349354