• Bisphosphonates,  Dentistry,  Fosamax,  Oral Bisphosphonates

    FDA Panel Says Bisphosphonates Need Label Changes on Use Duration



    This is the recommendation that came down today although the Food and Drug Administration does not have to accept the recommendations of its panels.

    Bone drugs from Warner Chilcott Plc, Roche Holding AG, Merck & Co. and Novartis AG need labeling changes to reduce the risk of fractures, a U.S. panel said.

    The companies should add clarifications on the length of time that osteoporosis patients may take the medicines, outside advisers to the Food and Drug Administration said today in a 17- 6 vote in Adelphi, Maryland. The FDA isn’t required to follow its panels’ recommendations.

    The agency has evaluated the safety of the drugs, known as bisphosphonates, for almost four years and cited possible links to unusual thigh fractures and jawbone deterioration in 2010. The agency said in July it also was examining conflicting studies on whether bisphosphonate pills such as Warner Chilcott’s Actonel, Merck’s Fosamax and Roche’s Boniva raise esophageal cancer risks.

    A revised label should “be very clear that efficacy may fall off after a period of time, perhaps five years,” panelist Lewis Nelson, director of the medical toxicology fellowship program at New York University, said after the vote. “Serious concerns have been raised about risk, and those need to be continually evaluated as well.”

    There needs to be additional research, period.

    Mere warning labels are not going to answer the questions from every day patients – how long do I take the medicine and what protocol do I use? Or, what is the chance my femur will fracture or will I develop osteonecrosis of the jaw (ONJ) if I have a tooth removed.

  • Pinboard Links

    Flap’s Links and Comments for June 6th on 11:24

    These are my links for June 6th from 11:24 to 11:39:

    • Vitamin D levels should be higher in people taking certain osteoporosis drugs, experts say – Vitamin D works with calcium to strengthen bones. But adequate levels of vitamin D in the bloodstream also appear to boost the power of bisphosphonates, medications used to treat osteoporosis, according to research presented Monday.

      The study adds to the evidence that the current recommendations for vitamin D may be too low. Late last year, the Institute of Medicine issued a report that declined to make changes to the recommendation — despite many new studies supporting the need for more vitamin D than is typically consumed.

      In the new study, presented at the annual meeting of the Endocrine Society, researchers found that having a circulating vitamin D level greater than 33 nanograms per milliliter was linked to a seven times greater likelihood of having a good response to bisphosphonates.

      Bisphosphonates include medications such as Fosamax, Boniva and Actonel. The standard vitamin D blood test measures a component called 25-hydroxy vitamin D.

      According to the IOM report, levels of 20 ng/ml to 30 ng/ml are adequate for most normal, healthy adults.

    • Illegal immigrants: Supreme Court allows California tuition policy for immigrants – The Supreme Court on Monday rejected a challenge to California's policy of granting reduced, in-state tuition at its colleges and universities to graduates of its high schools who are illegal immigrants.

      The justices turned down an appeal from lawyers for a conservative immigration-law group that contended "preferential treatment" for illegal immigrants violated federal immigration law. They cited a little-known provision in a 1986 law that barred states from giving "any postsecondary benefit" to an "alien who is not lawfully present in the United States ? on the basis of residence within a state."

      But last year, in the first ruling of its kind, the California Supreme Court said the state's policy did not conflict with federal law because the tuition benefit turned on a student's high school graduation, not his or her residency. In the 2001 law, the state said it would give in-state tuition to a qualified student who attended a high school in California for three years and graduated.

      Under this interpretation, a student from Oregon who graduates from a high school in California could obtain in-state tuition in the University of California system. In defense of its law, California education officials said that many of those who took advantage of its in-state tuition policy were U.S. citizens who hailed from other states.

      Overall, the state said about 41,000 students last year took advantage of this special tuition rule, but the vast majority of those were students at a community college. In 2009, the 10-campus UC system said 2,019 students paid in-state tuition under the terms of the state law. Of these, about 600 were believed to be illegal immigrants.

  • Bisphosphonates,  Dentistry

    Oral Hygiene and Antibiotics Play a Role in Healing and Pain Alleviation in Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)


    Osteonecrosis of the jaw in a patient who had poor oral hygiene and generalized periodontal disease and recently underwent routine dental extractions in the mandible. This patient had undergone monthly intravenous bisphosphonate therapy for treatment of multiple myeloma during the previous 12 months.
    Photo credit: Mayo Clinic

    According to this new paper here.

    Abstract

    OBJECTIVES:

    The objectives of this study were to define the incidence, pain, and healing in cancer patients treated with intravenous bisphosphonates.

    STUDY DESIGN:

    The study included long-term follow-up of 99 bisphosphonate-using patients (group A) and conservative treatment of 67 patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ, group B) using 3 antibiotic schemes and oral hygiene.

    RESULTS:

    The frequency of zoledronic acid single-agent use was 85.9% and 69.8% in group A and B, respectively. Median follow-up was 13 months (group A) and 16 months (group B). Two patients in group A developed BRONJ (2%). Of those with BRONJ in group B who completed follow-up, healing occurred in 14.9% (7/47) and pain subsided in 80.9% (38/47). Healing was significant in patients who received pamidronate followed by zoledronic acid (P = .023) and with BRONJ stages 0 and stage I (P = .003).

    CONCLUSIONS:

    This case series suggests that oral hygiene and conservative antibiotic therapy play a role in healing and pain alleviation in BRONJ. Oral hygiene and follow-up may decrease incidence of BRONJ.

    This sounds a reasonable course, knowing that this complication will be found to occur with increasing frequency. Let us hope a conservative protocol can be developed for these unfortunate patients.

    Previous:

    Jury Finds Novartis the Manufacturers of Zometa Not Liable for Osteonecrosis of the Jaw

    Osteonecrosis
    of the Jaw Associated With Bisphosphonate Agent Zoledronic Acid and
    Chemotherapy Combined With the Antiangiogenic Agent Bevacizumab

    Oral Bisphosphonates: Study – Absolute Risk for Femur Fracture Low with Bisphosphonates

    Revisiting Bisphosphonates and Femur Fractures

    Oral Bisphosphonates Associated with a SLIGHTLY Elevated Risk of Developing Osteonecrosis of the Jaw?

    New Dentistry Cause for Alarm for Patients Who Use Bisphosphonates – Fosamax, Actonel, Boniva?

    Dentistry Today: Bisphosphonates: Zometa (zoledronic acid) & Aredia (pamidronate disodium) Associated with Osteonecrosis of Jaw – REDUX

    Bisphosphonates: Zometa (zoledronic acid) & Aredia (pamidronate dis odium) Associated with Osteonecrosis of Jaw

  • Bisphosphonates,  Dentistry

    Jury Finds Novartis the Manufacturers of Zometa Not Liable for Osteonecrosis of the Jaw

    Osteonecrosis of the Jaw (ONJ)

    Another bisphosphonate law suit.

    A U.S. federal jury found that a bone drug made by Novartis Pharmaceuticals Corp was not to blame for the severe jaw deterioration developed by a Rhode Island man who died of cancer in 2005.

    Karleen Hogan, the widow of Timothy Hogan, claimed in a lawsuit filed in 2006 that Novartis had failed to properly warn her husband about the severe adverse effects caused by Zometa, a drug used to strengthen bones in cancer patients. She sought compensatory damages for her husband’s suffering.

    The suit is one of an estimated 600 filed against the unit of Novartis AG in recent years blaming the company for suppressing information about adverse effects linked to Zometa and Aredia, another bone-strengthening drug.

    I think what helped the defendants in this case was the testimony from the patient’s physican and dentist who said he had pre-exisiting dental problems and that the benefits of the drug outweighed the risks.

    But, there is a mixed record on these suits and there will be more to come.

    Hogan’s case was initially consolidated with hundreds of Zometa and Aredia liability suits in multi-district litigation in Tennessee federal court. Similar litigation is also pending in a state court in New Jersey.

    Hogan’s is the fourth Zometa case to go to trial. In October 2010, a New Jersey superior court jury ruled in favor of Novartis. A jury in Montana state court awarded a plaintiff with the same jaw disease $3.2 million in October 2009, and in November, a federal jury in North Carolina awarded a North Carolina woman’s family $12.8 million, later reduced to $1.26 million.

    Previous:

    Osteonecrosis of the Jaw Associated With Bisphosphonate Agent Zoledronic Acid and Chemotherapy Combined With the Antiangiogenic Agent Bevacizumab

    Oral Bisphosphonates: Study – Absolute Risk for Femur Fracture Low with Bisphosphonates

    Revisiting Bisphosphonates and Femur Fractures

    Oral Bisphosphonates Associated with a SLIGHTLY Elevated Risk of Developing Osteonecrosis of the Jaw?

    New Dentistry Cause for Alarm for Patients Who Use Bisphosphonates – Fosamax, Actonel, Boniva?

    Dentistry
    Today: Bisphosphonates: Zometa (zoledronic acid) & Aredia
    (pamidronate disodium) Associated with Osteonecrosis of Jaw – REDUX

    Bisphosphonates: Zometa (zoledronic acid) & Aredia (pamidronate dis odium) Associated with Osteonecrosis of Jaw

  • Bisphosphonates,  Dentistry,  Osteonecrosis

    Osteonecrosis of the Jaw Associated With Bisphosphonate Agent Zoledronic Acid and Chemotherapy Combined With the Antiangiogenic Agent Bevacizumab

    Osteonecrosis of the Jaw (ONJ)

    This study has just appeared in the Journal of the American Dental Association. Here is the abstract.

    Background. The authors investigated the incidence of and risk factors for osteonecrosis of the jaw (ONJ) in patients with metastases to the bone who received the bisphosphonate agent zoledronic acid (ZOL) and chemotherapy combined with the antiangiogenic agent bevacizumab (BEV).

    Methods. The authors evaluated 59 participants (34 with breast cancer and 25 with nonsmall-cell lung cancer). All of the participants received 4 milligrams of ZOL via intravenous (IV) infusion every four weeks and 15 mg per kilogram of BEV every three weeks. They conducted a dental examination in participants at baseline and every three months until the patients died or were lost to follow-up. If needed, participants received periodontal disease treatment and underwent tooth extraction before they started receiving ZOL and BEV.

    Results. The median time the participants received ZOL therapy was 18.8 months (range, 3.1–28.9 months); 36 participants (61.0 percent) received ZOL therapy for more than one year. The median time participants received BEV therapy was 16.7 months (range, 2.8–29.6 months). None of the participants required dentoalveolar surgery while undergoing cancer treatment. After a median follow-up period of 19.7 months, none of the participants developed bisphosphonate-related ONJ.

    Conclusions and Clinical Implications.
    ZOL combined with BEV did not predispose to ONJ participants with cancer that had metastasized to the bone who underwent a baseline dental examination and preventive dental measures. The study results must be considered in the context of the study’s protocols and the follow-up period.

    So, the question is whether these patients were prevented from developing osteonecrosis of the jaw (ONJ) because of the drug therapy or because of dental treatment protocols?

    The researchers took several measures to reduce the study participants’ risk of developing ONJ, including the following:

    • Dental caries and periodontal disease were treated before starting study treatment.
    • Mouth rinses with chlorhexidine and local antibiotic agents were administered before baseline oral hygiene.
    • Recommendations were made for maintaining good oral hygiene.
    • Teeth were extracted at least four weeks before starting ZOL and BEV therapy.
    • Invasive dental procedures were avoided during treatment.
    • If invasive dental procedures were needed during treatment, ZOL and BEV were readministered after at least four weeks.

    All the patients received a dental exam and panoramic x-rays before starting treatment and every three months until the patients died or were lost to follow-up. After a median follow-up period of 19 months, none of the study participants had developed ONJ.

    So, antiangiogenesis or treating the patient dentally prior to IV ZOL treatment?

    The jury continues to be out.

    But, preventive dental measures, including baseline dental examinations and follow-up are simple to institute and probably prudent, in any case.

    “Although further research is needed, the results of our study suggest that ZOL combined with the antiangiogenic agent BEV does not predispose patients with metastases to the bone from breast and NSCL cancer to ONJ if they undergo a baseline dental examination,” they concluded. “Nevertheless, the results of the study must be considered in the context of the follow-up period used in the study and the use of the preventive dental protocol.”

    Tanja Fehm, MD, from the department of obstetrics and gynecology at the University of Tübingen in Germany, has done similar research (Gynecologic Oncology, March 2009, Vol. 112:3, pp. 605-609). She told DrBicuspid.com that the incidence of ONJ is low — between 1% and 4% — in metastatic breast cancer patients receiving bisphosphonates.

    “Therefore, the number of patients (59) investigated in this study is too low to make meaningful conclusions,” she added. “However, the paper summarizes the preventive measures that can help avoid ONJ.”

    Previous:

    Oral Bisphosphonates: Study – Absolute Risk for Femur Fracture Low with Bisphosphonates

    Revisiting Bisphosphonates and Femur Fractures

    Oral Bisphosphonates Associated with a SLIGHTLY Elevated Risk of Developing Osteonecrosis of the Jaw?

    New Dentistry Cause for Alarm for Patients Who Use Bisphosphonates – Fosamax, Actonel, Boniva?

    Dentistry Today: Bisphosphonates: Zometa (zoledronic acid) & Aredia (pamidronate disodium) Associated with Osteonecrosis of Jaw – REDUX

    Bisphosphonates: Zometa (zoledronic acid) & Aredia (pamidronate dis odium) Associated with Osteonecrosis of Jaw

  • Pinboard Links

    Flap’s Links and Comments for May 6th on 08:32

    These are my links for May 6th from 08:32 to 08:45:

    • What Will Be the Future for Long Time Fosamax Users? – While jumping rope with the neighborhood children, a 59 year old Queens, New York woman felt her thigh bone snap. The pain was so severe that she fell to the ground as she readied for another jump. Sandy Potter had been diagnosed at the age of 48 with osteoporosis and began taking the drug Fosamax. She further stated that she had been on the medication for eight years prior to the incident and was now informed that her femur had snapped into two separate pieces.

      Fosamax is a commonly described drug used in the treatment of osteoporosis and contains bisphosphonates, which is used to slow the loss of bone and increase bone mass. Concerns about some of the side effects of Fosamax have been increasing and now there is mounting evidence that for some women that have been taking Fosamax for more than five years could be in danger of having fractures that are spontaneous in nature.

      According to Dr. Kenneth Egol, a professor of orthopedic surgery at NYU Langone Medical Center, over the last 18 months, femur fractures, such as the one in Sandy Potter’s case are occurring with more frequency
      Many patients claim that they were engaged in a low-impact exercise when they suddenly experience a break in the femur. What concerns Dr. Egol, is that because the femur is known as one of the strongest bones in the body, it should not be sustaining the damage that it has. Yet, people taking a leisurely walk or walking down a flight of stairs is experiencing this type of injury. Dr. Egol further stated that upon reviewing the X-rays taken of some of his patients, the images take on the appearance of an injury endured by a car accident rather than a minimal fall.

    • Dietary changes may preclude some prescriptions for osteoporosis, researchers say – While a number of prescription medications exist to reverse the bone loss associated with osteoporosis, a recent survey of medical literature indicated that many patients should first look into getting more calcium and vitamin D in their diets or through supplementation.

      Researchers from the University of Illinois at Urbana-Champaign stated as much in an article published in the journal Nutrients, where they noted that bisphosphonates may not rebuild the best sort of bone tissue, compared to adequate vitamins and nutrients in one's meals.

      In a meta-analysis of more than 200 research papers published in the prior 10 years, scientists found that the direction of medical inquiry has been increasingly swinging toward the initial use of calcium and vitamin D to treat osteoporosis.

      Co-author Karen Chapman-Novakofski said that a partial explanation for this trend appears to be the difference in bone quality between individuals on bisphosphonates and those eating a more complete diet or taking dietary supplements.

      "Bisphosphonates…disrupt normal bone remodeling by shutting down the osteoclasts – the cells that break down old bone to make new bone," she commented. "When that happens, new bone is built on top of old bone. Yes, your bone density is higher, but the bone's not always structurally sound."
      The National Osteoporosis Foundation states that bisphosphonates decrease the risk of hip fracture by up to 50 percent. However, the organization adds that some researchers have raised concerns that the drug class can occasionally lead to negative side effects, including thigh aches and broken femurs.By contrast, people over the age of 50 who take 1,200 milligrams of calcium and up to 1,000 international units of vitamin D each day may see gains in bone density with relatively few side effects, Chapman-Novakofski said.

    • Osteoporosis Drugs, Bisphosphonates Increases the Risk of Fractures – According to a new study at Sweden, it has been disclosed that osteoporosis drugs known as bisphosphonates is linked to the infrequent bone fractures. However, the risk of the fractures from osteoporosis drugs is very small in contrast to their benefits.

      The bone-building drugs bisphosphonates includes Aclasta, Actonel, Aredia, Bondronat, Boniva, Didronel, Fosamax, Fosavance, Reclast, Skelid, and Zometa.

      A Study Researcher and Professor of Orthopaedic Surgery at Linkoping University, Sweden, Per Aspenberg, MD, and PhD said that the risks of these drugs are very rare if it is prescribed correctly.

      The study, which was published in the New England Journal of Medicine, has included 12,777 women aged 55 and older, who suffered a fracture of the thigh bone in 2008. The study found that osteoporosis drugs are associated with the higher risks of fractures. The association among the bone-building drugs and fractures is very weak.

    • Bisphosphonate use and ?risk of atypical hip and ?femoral shaft fractures – Clinical question Do oral bisphosphonates increase the risk of atypical hip and femur fractures in postmenopausal women?

      Bottom line Oral bisphosphonate use for 5 years or longer is significantly associated with an increased risk of atypical hip and femur fractures (subtrochanteric or femoral shaft). A previous study (JAMA 2006;296:2927-2938) found little if any benefit of extended bisphosphonate use beyond 5 years in reducing the risk of typical fractures of the femoral neck or intertrochanteric region. Although this study design (case-control) is classified as weak evidence (LOE = 3b), it may be the best we have for some time. Thus, practicing clinicians should consider stopping bisphosphonates for most women after 5 years, except for those at high risk (eg, chronic steroid users). (LOE = 3b)

      Synopsis Current evidence on whether bisphosphonates increase the risk of subtrochanteric or femoral shaft fractures in postmenopausal women is uncertain. These investigators analyzed information obtained from multiple databases on the association between bisphosphonate use and fractures in a cohort of women in Ontario, Canada, 68 years or older, who initially started oral bisphosphonate (alendronate, risedronate, or etidronate) therapy between April 2002 and March 2008. Separate databases included information on drug prescriptions, hospitalizations, physician service claims, cancer, and basic demographic information. Cases included those women hospitalized with a subtrochanteric or femoral shaft fracture. Up to 5 women who were not hospitalized with similar fractures were matched to age and cohort entry date and served as control patients. Analyses were performed to adjust for other fracture risk factors. During the 7-year study period, 205,466 women commenced oral bisphosphonate therapy. Of these, 716 (0.35%) were hospitalized for an atypical subtrochanteric or femoral shaft fracture. The use of bisphosphonates for 5 years or longer, compared with transient or no use, was associated with a significantly increased risk of atypical hip or femur fracture (odds ratio [OR] = 2.74; 95% CI, 1.25-6.02). Among the 52,595 women using bisphosphonates for at least 5 years, a subtrochanteric or femoral shaft fracture occurred in 188 (0.36%) within 2 years. Duration of therapy of less than 5 years was not associated with an increased risk of fracture.

      Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783-789.