A recent NEJM article by Dennis Black MD denying a link between Fosamax and spontaneous mid-femur fractures has many doctors raising their eyebrows. Firstly, there is the problem of conflict of interest. The study was funded by Fosamax maker, Merck, and the authors are all on Merck's payroll.
Above left image fosamax induce fracture courtesy of Dr Lane Nejm .
Secondly, a number of flaws in the study are brought out by Dr Elizabeth Shane who says in a NEJM Editorial : No Xray data was presented, although every patient with a fracture had xrays. The women were on Fosamax for shorter time and lower dosage required to generate the femur fractures. The statistics of the study was questioned.
In spite of Dr Black's reassuring report, Dr Elizabeth Shane still recommends a drug holiday. This is a polite way of saying, "STOP THE DRUG". Dr Shane says: "it is reasonable to consider drug holidays "
I have a few more questions and comments about Dr Black's NEJM report.
1) The patient data was not stratified according to T score. The FIT trial showed increased fracture rates in patients on Fosamax with T scores greater than -2.5. Fosamax doubled the hip fracture rate in this group (T score above -2.5) from 6 to 11.
2) Although there were 284 hip fractures, 135 were excluded from the data for various reaons, and only 12 were accepted as spontaneous mid-femur fractures. Whenever data is excluded from a data set, this arouses suspicion and a red flag of possible data manipulation.
Another question: since there was no Xray data, how can the fractures be reviewed and excluded without this? If there was Xray review, then why wasn't this data included in the study?
3) Why do the results of Dr Dennis Black contrast with the many reported case series on Fosamax induced spontaneous femur fractures from Joseph Lane , Odvina and Goh (and many others).
Dr Black's results run counter to the experience of the medical community. Physicans are seeing and reporting more cases of atypical femur fractures on Fosamax. We never saw these before the fosamax era.
4) Why do the results of Dr Dennis Black contrast with bone histology studies that show abnormal bone formation on Fosamax, reporting "microdamage accumulation and reduced some mechanical properties of bone".
5) Why are these spontaneous mid-femur fractures happening at all ? Doesn't this indicate a severe problem with the underlying bone physiology? The bisphosphonate drug is producing abnormal, pathological bone demonstrated on histology slides. Dr Black's report does not address this question.
6) What about reports of a link with Osteonecrosis of the Jaw , another example of fosamax disturbing bone physiology, making the bones weaker, not stronger. Dr Black's report does not address this issue.
Bottom line: Dr Black's report is unconvincing. Especially unconvinced are the increasing numbers of women presenting to the orthopedic surgeons with spontaneous femur fractures on fosamax. These fractures are devastating and do not heal.
http://content.nejm.org/cgi/content/full/NEJMe1003064 Evolving Data about Subtrochanteric Fractures and Bisphosphonates Elizabeth Shane, M.D. - it is reasonable to consider drug holidays with careful observation for most patients with osteoporosis who are receiving long-term therapy
http://content.nejm.org/cgi/content/full/NEJMoa1001086 Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Dennis M. Black, Ph.D., Michael P. Kelly, M.D., Harry K. Genant, M.D., Lisa Palermo, M.A., Richard Eastell, M.D., Christina Bucci-Rechtweg, M.D., Jane Cauley, Ph.D., Ping Chung Leung, M.D., Steven Boonen, M.D., Ph.D., Arthur Santora, M.D., Anne de Papp, M.D., Douglas C. Bauer, M.D., for the Fracture Intervention Trial and HORIZON Pivotal Fracture Trial Steering Committees Conclusions The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions.
Dr. Black reports to the NEJM that he is receiving grants (to UCSF) from Merck, Novartis, Amgen, and Roche and travel reimbursements from Merck and Novartis, who also supported the research. The study was sponsored by Merck and Novartis. Several other authors work for the companies, while others consult and receive compensation for their work from the makers of bisphosphonates.
http://content.nejm.org/cgi/content/full/358/12/1304 NEJM V358:1304-1306 March 20, 2008 Number 12 Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate Brett A. Lenart, B.S., Dean G. Lorich, M.D. ,Joseph M. Lane, M.D. ,Weill Cornell Medical College ,New York, NY 10021
http://www.ncbi.nlm.nih.gov/pubmed/18222447 An emerging pattern of subtrochanteric stress fractures: A long-term complication of alendronate therapy?§ Ernest Beng Kee Kweka,*, Seo Kiat Goh a, Joyce Suang Bee Koh a, Meng Ai Png b, Tet Sen Howe Department of Orthopaedic Surgery, Singapore General Hospital, Outram Road, Singapore 169608, Singapore Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore August 2007 Injury, Int. J. Care Injured (2008) 39, 224—231
http://www.ncbi.nlm.nih.gov/pubmed/19884427 J Bone Joint Surg Am. 2009 Nov;91(11):2556-61. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. Capeci CM, Tejwani NC.Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, 301 East 17th Street, Suite 1401, New York, NY 10003, USA.
http://www.ncbi.nlm.nih.gov/pubmed/19198962 Clin Orthop Relat Res. 2009 Jul;467(7):1921-6. Epub 2009 Feb 6. Case reports: two femoral insufficiency fractures after long-term alendronate therapy. Sayed-Noor AS, Sjödén GO.Department of Orthopaedic Surgery, Sundsvall Hospital, 851 86 Sundsvall, Sweden.
http://www.ncbi.nlm.nih.gov/pubmed/19670917 Drug Saf. 2009;32(9):775-85. doi: 10.2165/00002018-200932090-00002. Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital. Ing-Lorenzini K, Desmeules J, Plachta O, Suva D, Dayer P, Peter R. Division of Clinical Pharmacology and Toxicology, Regional Pharmacovigilance Centre, University Hospitals of Geneva, Geneva, Switzerland.
http://www.ncbi.nlm.nih.gov/pubmed/20020334 Clin Orthop Relat Res. 2009 Dec 18. [Epub ahead of print] Case Reports: Subtrochanteric Femoral Stress Fractures after Prolonged Alendronate Therapy. Cermak K, Shumelinsky F, Alexiou J, Gebhart MJ. Department of Orthopedic Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1 rue Heger-Bordet, 1000, Brussels, Belgium,
Bone Histology studies
Suppressed Bone Turnover by Bisphosphonates Increases Microdamage Accumulation and Reduces Some Biomechanical Properties in Dog Rib , Journal of Bone and Mineral Research Volume 15 Issue 4, Pages 613 - 620 Published Online: 18 Feb 2010
Tasuku Mashiba 1, Toru Hirano 1, Charles H. Turner 1, Mark R. Forwood 2, C. Conrad Johnston 3, David B. Burr, Ph.D. 1 * 1Departments of Anatomy and Cell Biology, and Orthopaedic Surgery, Biomechanics and Biomaterials Research Center, Indiana University School of Medicine, Indianapolis
It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three-point bending. Total cross-sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One-year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.
http://www.annals.org/content/144/10/753.abstract Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws Sook-Bin Woo, DMD; John W. Hellstein, DDS, MS; and John R. Kalmar, DMD, PhD Annals of Internal Med May 16, 2006 vol. 144 no. 10 753-761
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