Bone Health and Osteoporosis

More than half of all Americans 50 years old or older either have, or are at significant risk of getting, osteoporosis, a systemic bone disorder characterized by decreased bone mass and deterioration of bone architecture  (tissue) leading to more fragile bones and a higher risk of bone fractures with even minor trauma.  According to the National Osteoporosis Foundation (NOF), an estimated 10 million (one in ten) Americans have osteoporosis, 80% of whom are women, while another approximately 34 million have clinically low bone mass, measured and tested as Bone Mineral Density (BMD), putting them at elevated risk of the disease; these 34 million have what is called osteopenia. 

      Each year there are about 1.5 million osteoporosis-related fractures, and about 300,000 people who suffer such a fracture die of injury-related complications, according to the Report of the Surgeon General's Workshop on Osteoporosis and Bone eaH Health, and one of five people die within a year after sustaining a hip fracture.  It's startling to observe, but true, that more people overall die in six months of a hip fracture and its complications than die in ten years from stage I (early) breast cancer. Seen another way, a 50 year old woman's lifetime risk of dying from a hip fracture is about equal to her risk of dying from breast cancer (all stages), and about 4 times as great as dying from endometrial cancer!  Conclusions: Older women are at a greater risk of death following hip fracture compared to breast cancer. Increased awareness of mortality associated with hip fracture is needed to promote preventive measures.

The Bisphosphonates   

      Most people with osteoporosis, or who have a precondition called osteopenia that puts them at increased risk of osteoporosis and bone fractures, will be treated with a combination of calcium and Vitamin D, and an anti-osteoporotic agent.  By far the most commonly prescribed drugs for the treatment of osteoporosis are the bisphosphonates which include the third generation agents alendronate (Fosamax®), risedronate (Actonel®), the recently introduced ibandronate (Boniva®), as well as older second generation agents like zoledronic acid (Zometa®) and pamidronate (Aredia®),  these being used more commonly to treat bone metastasis in various cancers.

Table 1 - Common Bisphosphonates

Bisphosphonate	Trade Name
First Generation
Clodronate	Bonefos® *
Etidronate	Didronel® oi
Second Generation
Pamidronate	Aredia® i
Zoledronic acid	Zometa® i
Third Generation
Alendronate	Fosamax®
Ibandronate	Boniva®
Risedronate	Actonel®
Tiludronate	Skelid® **
*     primarily used in Europe and Canada **    used to treat Paget's Disease (a bone disorder)i     intravenously administered oi   oral or intravenous

      The bisphosphonates have, all told, served patients well: to varying degrees they increase bone mineral density (BMD) and reduce the risk of  vertebral (that is, spinal) fractures, and some, but not all, also reduce the risk of non-vertebral fractures such as wrist and rib, including the most serious fractures, those of the hip.

Trouble in Paradise: First Sightings

However, in 2003 sporadic case reports began to appear in the medical literature of bisphosphonate-treated patients with a strange new clinical entity, necrosis (death of tissue) of the jaws, following dental procedures and usually manifesting as  localized pain, exposed bone in the oral cavity, numbness and/or altered sensation, oral infection, and slow healing. To date there have been over 200 cases of this condition, with new cases reported every day, the earliest dating  back to 2001. The condition is usually called osteonecrosis of the jaw (ONJ), or sometimes  bisphosphonate-associated osteonecrosis (BON), or  avascular necrosis of the jaw: avascular necrosis is the loss of the blood supply to the bones, causing the bone tissue to die and the bone to collapse.

      Note that the introduction of these cases coincides with the increasingly widespread use of the new (second, and especially third) generation of bisphosphonates as the population continues to age and more people are prescribed these drugs for bone health. 

      One of the earliest ONJ reportings was by J Wang and colleagues who observed it in three women undergoing chemotherapy for metastatic breast cancer, all of whom were on intravenous Aredia. Although two developed jaw necrosis after tooth extractions, what was sobering was that the third patient appears to have developed the condition spontaneously.

      Other instances of ONJ then began to be reported rapidly, from Robert E Marx, DDS, at the University of Miami, who had previously studied a related condition called osteoradionecrosis affecting patients undergoing radiation therapy for cancer of the head and neck; from Salvatore Ruggiero, MD at Long Island Jewish Medical Center, who documented 36 patients who had developed ONJ while being treated with intravenous bisphosphonates for metastatic bone disease and osteoporosis, most of whom developed ONJ after dental extraction procedures, but again, disturbingly, in about 30% of whom ONJ developed spontaneously, and from many others.             

A Growing Epidemic

The floodgates were open and many other reports now began to pore in from across the world, from researchers in Tel Avid, Valencia (Spain), and South Australia. The Australian team  documented ONJ presenting as painful bone exposure after dental extraction, including an early and surprising case of this disorder in one patient not on an intravenous bisphosphonate, but rather on orally administered alendronate (Fosamax),  and Israeli researchers also reported another 3 cases of ONJ associated with Fosamax.  This was a new appreciation: before this it was thought that ONJ was only associated with intravenous bisphosphonates, not with the orally administered third generation of agents like Fosamax, Actonel and Boniva.  Indeed, it now appeared from the daily reports of ONJ that the subtitle of one paper (Dr. Marx) in 2003 on ONJ - "a growing epidemic" - was no exaggeration.  

Early Clues

      The first thing that was noticed was that the patients in these early cases were all receiving bisphosphonates, and most were furthermore cancer patients, especially with bone metastases from breast or prostate cancer, or patients being managed for multiple myeloma, a cancer of the plasma cells of the bone marrow. The skeletal events of these patients were mostly being treated with the intravenously (IV) administered bisphosphonates, pamidronate (Aredia) and zoledronate (Zometa). We now know in retrospect that the incidence of ONJ in cancer patients on IV bisphosphonate  therapy appears to be about 4%-10%.

      But we now know more: that although possibly to a lesser degree, the widely used oral bisphosphonates have also been implicated in ONJ.  And even the very recently introduced ibandronate (Boniva) was not exempt: researchers in Germany reported a case of ONJ in a woman with breast cancer using Boniva.

      Further, although some patients with no relevant history of recent dental or oral procedures seemed to develop ONJ anyway, the majority - at least 70%  to 80% - seemed to be precipitated by tooth extractions, a now recognized risk factor.

Risk Factors for ONJ

      One of the most powerful risk factors for contracting ONJ while on bisphosphonate therapy is cancer. Researchers analyzed the General Practice Research Database (GPRD) which contains medical data on about. 5.5 million UK patients, and found the incidence of osteonecrosis to be 4 times higher in the population of cancer patients than in the general population, likely in part due to the compromise to the immune system from various toxic oncotherapies (therapies for cancer). So other potentially immunosuppressive disease states or therapies can also put a patient at risk; these include infections, including HIV, and steroid therapy used in many medical conditions.  And note that there is some recent evidence from Maria Sarasquete and Ramon Garcia-Sanz and their colleagues in Salamanca, Spain that genetics can also play a role in the development of ONJ, and in addition Vicenzo Adamo and colleagues in Messina, Italy suggest that certain cancer treatments, like chemotherapy and therapy with what is known as antiangiogenic agents like Avastin may also play a contributing role. 

      One the other side, namely as to the bisphosphonates themselves, the intravenous agents pamidronate (Aredia) and zoledronic acid (Zometa) are far more likely to be associated with ONJ than are the commonly prescribed third generation oral agents like alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva), and the risk increases with longer duration of treatment and with higher doses.  But remember, ONJ has been documented, admittedly to a considerably lesser degree, with the oral third generation bisphosphonates, as well as on standard doses and for treatment durations as short as 6 months.

      Finally, oral/dental and periodontal procedures and disorders also highly increase the risk of developing ONJ while on bisphosphonate therapy, whether that therapy is for cancer bone metastasis, Paget's disease (a bone disorder), osteoporosis, or any other disorder for which bisphosphonates are used. The highest risk is with tooth extractions, but also gum or oral infections, poorly fitting dentures, major dental or periodontal surgery and dental trauma.

Regulation: Awakening the FDA

      Some warning were finally issued under the dedicated prompting of the oral surgeons Dr. Salvatore Ruggiero and Dr. Robert Marx, both to the FDA, through the FDA's MedWatch adverse events reporting system, and also directly to the manufacturer of the two intravenous bisphosphonates, Novartis.

On the regulatory side, the FDA in late 2004 directed Novartis to send a "Dear Doctor" letter warning doctors and dentists about the ONJ-bisphosphonate  problem, and on the  consumer side, Novartis included a warning statement in the package inserts of both products.

      Both alerts only mention the association of ONJ with intravenous bisphosphonates, despite the documented fact that ONJ has also been associated with oral bisphosphonates (Fosamax, Actonel, and Boniva). Fortunately for consumers, although not required by FDA regulatory action, Merck, the manufacturer of alendronate (Fosamax) has voluntarily included a comparable warning in the package insert for their orally administered product., as have the makers of risedronate (Actonel) and ibandronate (Boniva).  And several lawsuits are currently being mounted in connection with sustained ONJ injury.

Pre-Bisphosphonate Preventative Measures

      Why is this relatively rare but increasing hazard of ONJ so serious for the consumer? One reason is that  the use of bisphosphonates is currently massive, and rising as the population ages and osteoporosis and other bone disorders, including cancer-related bone metastasis, become more common - Fosamax for example is among the top 20 best selling drugs.  Another more sobering reason is unfortunately until recently ONJ has been considered both irreversible and typically progressive, and with more cases being reported daily. But recent advances have brought some highly promising treatments for ONJ, which we discussed fully below. Nonetheless, preventative measures are paramount in dealing with the risk of ONJ.

      Fortunately there are many things a consumer can do to minimize the risk of developing ONJ, and the most critical are outlined in table 4, below.  However, before any prophylactic health measures can be taken, it's imperative that all present or pending users of bisphosphonates learn about ONJ, especially the most likely signs and symptoms of this disorder, so as to be able to immediately report them to their oral/dental health professionals.  This is especially important for immuno-compromised patient populations, such as cancer patients and others at high risk (see Table 3 for the most critical risk factors).

Alternatives to Bisphosphonates

      Although bisphosphonates are the mainstay of osteoporosis therapy, being both highly effective and relatively safe, they are not the only anti-osteoporotic agents. Table 5 below briefly notes some non-bisphosphonate agents used in the treatment of osteoporosis and related bone disorders.

Table 5 - Alternative Osteoporosis Drugs]

Agent	Trade Name
Raloxifene	Evista®
Calcitonin	Miacalcin®
Parathyroid Hormone (PTH)	Teriparatide®
Strontium Ranelate	PROTELOS® *
Tibolone	Livial® *
*     Not yet available in US, pending FDA approval

Although it's beyond the scope of this report to examine the tradeoffs of these bisphosphonate alternatives, they can and should be raise with your health professional, and there is a full discussion on Osteoporosis Watch (see our Resources section at the end of this report).

New Hope for Early Detection: Testing for the Risk of ONJ

      Robert Marx chief of oral and maxillofacial surgery at the University of Miami and some other experts suggest the use of a bone marker known as CTX (serum C-terminal cross linking telopeptide, or more simply C-telopeptide) to both measure patient progress on oral bisphosphonates, and as an estimate of risk for such a patient to develop ONJ, and a recently published report by Dr. Marx in the Journal of Oral and Maxillofacial Surgery appears to confirm the usefulness of this simple test which is performed as a morning fasting serum (blood) test. Any patient with CTX values below 100 pg/mL is considered at high risk, in contrast to patients with values above 300 pg/mL who are considered to not have any significantly elevated risk of developing ONJ; CTX values between 100 pg/mL and 150 pg/mL would represent moderate risk. The CTX test may be especially valuable for patients who have been on bisphosphonates long-term, meaning 3+ years, and because CTX values rise - which is good - for each month when the patient is on a drug holiday from the bisphosphonate agent, that can help guide dental professionals as to when the safest time would be to schedule any dental surgical procedures.   

Dr. Marx further advises that a drug holiday - a temporary discontinuation of bisphosphonate treatment should be instituted whenever a CTX value falls below 150 pg/mL, and that another CTX test should be taken after  4 to 6 months of such a drug holiday to determine whether to reinstitute the therapy of continue the drug holiday for another 4 months, the latter being advised if the CTX value remains below 150 pg/mL, with the CTX test being repeated at that point. 

Treating ONJ

• New Hope for Local Therapy of ONJ
  Intermittent or continuous antibiotic therapy may be of value to prevent (further) infection, possibly supplemented with an oral chlorhexidine (Peridex®) rinse. Furthermore, and more optimistically, a review undertaken by Breast Cancer Watch / Osteoporosis Watch (C Kaniklidis, reviewer) uncovered a valuable clue, evidence that in cases of ONJ, a microbe, the gram positive bacterium Actinomyces, frequently an opportunistic pathogen especially of the oral cavity, attached to the necrotic bone tissue. And given this, we further uncovered that besides oral rinsing with chlorhexidine (Peridex, Corsodyl, Savacol) and systemic antibiotic therapy, the good news is that two non-prescription agents are also active and effective against various forms of orally resident Actinomyces:
  
  
  1. a baking soda] toothpaste containing 52% baking soda and 3% sodium percarbonate (Arm & Hammer PeroxiCare) as well as another dentifrice containing 65% baking soda (Arm & Hammer Dental Care) resulted in statistically significant reductions in the levels of Actinomyces species); and
     
     
  2. the antimicrobial mouth rinse Listerine, extraordinarily, completely eradicated a broad spectrum of oral microorganisms in 10 to 30 seconds, including Actinomyces, and may even be effective in providing some significant analgesia, probably due as the study author speculate to a decrease in oral bacteria by the antimicrobial action of Listerine, leading to lowering the inflammatory response of the host.
     
     Given this, Breast Cancer Watch / Osteoporosis Watch now believes that we can no longer consider bisphosphonates by themselves as the sole cause of ONJ, but rather must acknowledge the joint role that oral pathogens, in particular Actinomyces, play in the development of osteonecrosis of the jaw, and if this is correct, it suggests the vital positive role of anti-bacterial therapy in minimizing or remitting adverse symptoms, and possibly in also prophylactically minimizing the potential for even contracting ONJ while on bisphosphonate therapy.
     
     
• New Hope for Treating ONJ: Ozone Therapy
  Although it was originally thought that ozone therapy was of no appreciable value in treating ONJ, recent research has established that this century old therapy is indeed of benefit for ONJ sufferers. Ozone is essentially a form of oxygen with an extra oxygen molecule attached, so oxygen is O₂ and ozone is O_3.  Ozone is produced naturally by lightning, and also by ultraviolet radiation from the sun transforming oxygen in the higher atmosphere to ozone, hence the "ozone layer". So how does ozone have any benefit in ONJ?  In part as a result of the known antimicrobial and wound-healing properties of ozone, as shown by Italian researchers Maria Teresa Petrucci, Alessandro Agrillo and their colleagues who designed a special 15-day course of antibiotics, surgery and ozone therapy in a dozen patients with ONJ.  The results were impressive, with eight (75%) patients achieving complete response, the other four (25%) still significant partial response, but with all patients dramatically relieved of the pain, secretions and the halitosis common in ONJ.   
  
• Minimal reduction (called debridgement) of the exposed bone may be undertaken be an oral surgeon solely to reduce sharp edges so as to reduce trauma to surrounding or opposing tissues.
  

Open Questions and Issues

• The big questions remaining are:

  1.       If ONJ develops, should the bisphosphonate be discontinued?
  2.       Should the bisphosphonate be discontinued before undergoing invasive dental/oral procedures?

• At present, there is no evidence that interrupting the bisphosphonate therapy will prevent or lower the risk of ONJ, or facilitate symptomatic treatment once ONJ develops.  The reasons for this appear to be twofold:
  (1) bisphosphonates have quite long-term activity and residence in the system, typically for years, and
  (2) bisphosphonates actually merge into and so become part of the bone mineral matrix, making it unlikely that intermission or even termination would have any clinically significant or beneficial impact on outcome.
  
• Finally, the benefits of  osteoporosis therapy, especially in terms of reduction of the risk of fracture, as well as its value in the specialized context of treating  certain cancers, generally outweigh the relatively small risk of ONJ.

Final Clues and a Potential New Option

      There is one other twist to the mystery of ONJ, one the current author was personally involved in recently as part of his breast cancer research. Many breast cancer patients require bisphosphonates for either (1) the treatment of osteoporosis, often induced by chemotherapies that are associated with bone loss as part of their anti-estrogenic activity, or cause a premature menopause state, or (2) to help treat bone metastasis.  Given the association of bisphosphonates with OJN, I conducted a systemic review of the medical literature and began to notice that there were no cases of ONJ associated with three of the eight major bisphosphonates in use worldwide, namely, clodronate (Bonefos), etidronate (Didronel), and Tiludronate (Skelid).

What was different about these bisphosphonates?  The research suggested the answer: they all are non-nitrogen-containing in terms of their chemical structure, while all the others contain a nitrogen ring chemically.  But it's not important to understand nitrogen rings and chemical structure: the point is that ONJ is solely associated with nitrogen-containing bisphosphonates.  The practical upshot is that there is, because of this, another possible alternative for avoiding the risk of ONJ. 

      Of the three non-nitrogen bisphosphonates, the most promising for may be clodronate (Bonefos), which has proven efficacy against all types of fractures. It was until recently only available in Europe and Canada, but it was approved by the FDA in January 2005 for the treatment of  bone metastasis of breast cancer, and may later be approved for other bone disorders like osteoporosis, becoming a viable and effective osteoporosis therapy without the risk of ONJ.

Consumer Summary

References

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10. Facts and statistics about osteoporosis and its impact. Available at: http://www.iofbonehealth.org/facts-and-statistics.html.  Accessed Jan 4, 2008.
11. America's Bone Health: The State of Osteoporosis and Low Bone Mass In Our Nation. National Osteoporosis Foundation (NOF). Available at: http://www.nof.org/advocacy/prevalence/index.htm. Accessed Jan 4, 2008.