Fosamax, Actonel, Osteoporosis and Toulouse Lautrec
by Jeffrey Dach M.D.
Viewing Osteoporotic Compression Fractures All Day
While working as a radiologist for 25 years, a large part of my day was spent reading X-rays of osteoporotic compression fractures of the spine, which was quite common. These fractures typically involve the mid thoracic spine causing loss of height and curvature of the spine, and considerable pain.
Above left image: Dexa scan for osteoporosis, courtesy of wikimedia commons
Vertebroplasty for Compression Fracture – Barbaric?
Working in the hospital over the years, I saw many procedures come and go. A procedure called vertebroplasty, still in vogue, is used for treatment of compression fractures. This involves injecting glue into the collapsed vertebral body under X-Ray control.(1) Although the procedure may seem somewhat barbaric, it does provide pain relief and restores some height to the collapsed vertebral body. The vertebroplasty procedure was invented in 1984 by the French and introduced into the US by Mary Jensen MD. The procedure is not for the light hearted because during the actual acrylic glue injection, the acrylic cement may flow into the epidural venous plexus leading to venous thrombosis or pulmonary embolus.(2) The more refined Kyphoplasty version involves inflation of a balloon device to expand the collapsed vertebral body just prior to injection of cement into the cavity. The procedure is quite good at providing some form of pain relief from the compression fractures.
2009 update: Vertebroplasty Procedure Discredited by Two Studies Published in NEJM (17,18)
In one Australian study, there was:
“no beneficial effect of vertebroplasty as compared with a sham procedure” and in the other study, results were “similar to the improvements in a control group.”(17-18)
Prevention Makes More Sense
On the surface, it might appear callous for the medical system to wait years until thousands of women develop severe osteoporosis with compression fractures, and then intervene with glue injections. Perhaps some form of prevention would make more sense. The usual preventive recommendation to take calcium tablets apparently was not effective for these women presenting with osteoporotic compression fractures. Perhaps the best preventive plan can be found in Russell Jaffe’s article, Acid-Alkaline Balance and its Effect on Bone Health.(3) see this link: Acid_Alkaline Balance Bone Health Brown Jaffe 2000.
Russell Jaffe MD is a charming and humorous fellow who informed our small group of docs at his medical seminar that in the old days he ran a lab at the NIH, and was actually offered the job of Assistant Surgeon General, but he declined the offer after trying it for a day. He is also the founder of a supplement company called Perque.(15)
Excess Acid in the American Diet Causes Osteoporosis
According to Dr. Jaffe’s article, excess acid production from the American diet causes the chronic calcium loss leading to osteoporosis.(3) The calcium is pulled away from the bones, and used up as a buffering agent for the acids which can then be excreted in the urine. The solution is to alkalinize the diet, and with the help of alkaline food charts, and pH test strips along with the usual calcium and vitamin supplements, osteoporosis can be arrested and gradually reversed in a process which may take years. I would add that a bio-identical hormone program is also useful for preventing and reversing osteoporosis.
Bisphosphonate Drugs and Toulouse Lautrec’s Genetic Bone Defect
For the impatient ones who wish to see a prompt increase in bone density, the FDA approved the bisphosphonate drug Fosamax (alondronate) which was first introduced in 1995. Merck made $3.2 Billion Dollars on 22 million Fosamax prescriptions in 2006. A major drug study, (FIT) the Fracture Intervention Trial, showed lower fracture rates in the drug group.(4) And it is true that the bisphosphonate drugs will reward the user with a prompt increase in bone density. The main question remains however, how strong is the bone with the increased density? This is an important question because we know from studies of Toulouse Lautrec that his increased bone density was not stronger, in fact his bones were much weaker leading to spontaneous fracture and jaw necrosis. This is explained below.
short stature from pycnodysostosis.
Genetic Bone Disease Duplicates Action of Fosamax
What could Fosamax (alondronate) have in common with Toulouse Lautrec, the famous French Impressionist artist? One day, Toulouse Lautrec’s name came up in conversation, and we puzzled over the cause of Lautrec’s short stature. After looking up the question on the internet, we discovered that Toulouse Lautrec’s parents were first cousins giving Toulouse the autosomal recessive genetic disease, pycnodysostosis, which means dense bones. I had seen X-Rays of this bone disease in text books while studying for the radiology board exams, but I have never seen it in actual practice.
Dr. Gelb found Toulouse Lautrec’s dense bone disease was caused by a genetic defect in cathepsin K, a protease enzyme of the osteoclast cells responsible for removing and remodeling bone.(5)(6) Osteoclast cells are bone cells involved in resorption and remodeling of bone. In this disease, the genetically abnormal bone is very dense on xrays, and yet looking under microscopic examination, one sees profound deterioration in trabecular architecture and lamellar arrangement. This is presumably the reason for spontaneous fracture and jaw necrosis which occurs in Lautrec’s genetic bone disease, and also occurs as an adverse side effect of the bisphosphonate drugs.(7)
This osteoclast dysfunction and resulting bone fragility explains why Toulouse had spontaneous fractures of both mid femurs at the age of 12 and 14. The mid-femur fractures never healed properly. The non-healing mid femur fractures caused Toulouse Lautrec to have short stature, attaining a final height of only four and a half feet.(8)
Courtesy of Taylor et al. J Bone Joint Surg Am 60 (8): 1128.
Bisphosphonate Mechanism of Action – Same as Lautrec’s Defect
Bisphosphonate drugs (fosamax and actonel) are taken up by osteoclasts, causing disruption of osteoclast activity. The osteoclasts are bone cells involved in bone resorption and remodeling. This loss of the osteoclast activity inhibits bone resorption and bone remodeling, tasks otherwise performed by the osteoclasts.(9)
Thus, the bisphosphonate drugs produce a chemical disruption of osteoclast activity same as the genetic disease of Toulouse Lautrec. The bisphosphonate drugs also produce the same adverse side effects, namely jaw necrosis and spontaneous fracture.
Questions About Long Term Safety of Bisphosphonates
The conventional medical test for bone density is the DEXA bone scan. And, indeed DEXA bone scanning does confirm that bisphoshonate drug treatment increases bone density, and studies such as the FIT (Fracture Intervention Trial) report drug treatments reduce fracture rates in severely osteoporotic women over the short term. However, Susan Ott, MD raises questions about the long term safety of bisphosphonates. Although the bisphosphonate drugs appear to have short term benefits, Dr. Susan Ott speculates that over the long term, after 5 years of use, the drugs cause severe suppression of bone formation, and negative effects such as microdamage and brittleness.(10)
Reports of Spontaneous Fractures
Jennifer P. Schneider, MD, PhD reports a 59-year old previously healthy woman on long-term alendronate.(11a,11b) While on a subway train in New York City one morning, the train jolted, and the woman shifted all her weight to one leg, felt a bone snap, and fell to the floor, suffering a spontaneous mid -femur fracture (see right image). In the months following, it became clear that the fracture was not uniting.
Left Image: Spontaneous mid femur fracture courtesy of Jennifer P. Schneider, MD, PhD January 2006 Volume 61, Number 1 Geriatrics
Schneider speculates that increased bone density from the bisphosphonate drug does not necessarily equate with good bone quality. By decreasing osteoclast activity and bone resorption, and therefore bone formation as well, microdamage, and brittle bone may result in fractures.(11a, 11b)
In 2010, Dr. Odvina reports on a series of 9 patients who suffered spontanous fracture while on fosamax (alendonate). Five of the nine cases were spontaneous mid femur fractures. Two had bilateral mid femur fractures just like those sustained by Toulouse Lautrec. Six of the fractures showed delayed or absent fracture healing. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, and Odvina raised the possibility that severe suppression of bone turnover could develop during long-term fosamax (alendronate) therapy, resulting in increased susceptibility and delayed healing of fractures.(12)(22)
Dimitrakopoulos report on 11 patients presenting with necrosis of the jaw, claiming this to be a new complication of bisphosphonate therapy administration, i.e. osteonecrosis of jaws. He advised clinicians to reconsider the merits of the rampant use of bisphosphonates. Osteonecrosis of the jaw is a common finding in pycnodysostosis. The bisphosphonates recreate the same clinical profile of spontaneous mid femur fractures, failure of bone healing and jaw necrosis which tormented Toulouse Lautrec.(13)
In spite of these widely adverse effects of bisphosphonates, there are four more drugs in clinical trials specifically designed to inhibit cathepsin K, the enzyme defect in Lautrec’s genetic bone disease.(14)
FDA approval for use in osteoporosis treatment is expected. Excuse me here, but perhaps this thinking needs re-evaluation. In essence, these drugs are creating a population of women with Toulouse Lautrec’s bone disease.
Ironically, women who sustain fractures while on Fosamax are told by their docs that the fractures are due to the underlying osteoporosis, not the drug. For a recent example that I know of, a 60 year old female sustained a fractured elbow after minor trauma at home in the kitchen. She claims that, if not for the biphosphonate drug, her fracture would have been much worse. When patients continue to fracture while on the bisphosphonate drugs, the medical system tends to blame it on the underlying osteoporosis, not the drug. Sound familiar?
The obvious conclusion is that this entire class of bisphosphonate drugs should be pulled from the market. However, there is too much money at stake, and the powerful Drug Industry will have their way.
Links to Articles With Related Content:
The New Osteoporosis Drugs the Good, Bad and Ugly
References and Links
(1) Treatment of Chronic Symptomatic Vertebral Compression Fractures with Percutaneous Vertebroplasty1, Daniel B. Brown Louis A. Gilula Manu Sehgal Joshua S. Shimony, AJR 2004;182:319–322
Vertebroplasty and Kyphoplasty, Percutaneous Article Last Updated: Jul 27, 2006 Jeffrey P Kochan, MD, Associate Professor of Radiology and Neurosurgery, Temple University School of Medicine; Director, Diagnostic and Interventional Neuroradiology, Department of Radiology, Temple University Hospital
(3) Acid_Alkaline Balance Bone Health Brown Jaffe 2000
Acid-Alkaline Balance and Its Effect on Bone Health Susan E. Brown, Ph.D., CCN, and Russell Jaffe, MD, Ph.D., CCN International Journal of Integrative Medicine Vol. 2, No. 6 – Nov/Dec 2000
Lancet. 1996 Dec 7;348(9041):1535-41 Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE.
Am J Hum Genet. 1998 April; 62(4): 848–854. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. B D Gelb, J P Willner, T M Dunn, N B Kardon, A Verloes, J Poncin, and R J Desnick Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.
OMIMTM – Online Mendelian Inheritance in Man TM #265800 GeneTests, PYCNODYSOSTOSIS A number sign (#) is used with this entry because pycnodysostosis can be caused by mutation in the cathepsin K gene (CTSK; 601105).
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1538-1547
CLINICAL CASE SEMINAR Decreased Bone Turnover and Deterioration of Bone Structure in Two Cases of Pycnodysostosis Nadja Fratzl-Zelman, Angelika Valenta, Paul Roschger, Alexander Nader, Bruce D. Gelb, Peter Fratzl and Klaus Klaushofer
Russell, R. Graham G. “Bisphosphonates From Bench to Bedside.” Skeletal Development and Remodeling in Health, Disease and Aging 1068 (2006): 367-401. Bisphosphonates Bench to Bed Side Russell R Graham 2006
(10) http://jcem.endojournals.org/cgi/content/full/90/3/1897 The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1897-1899 Long-Term Safety of Bisphosphonates, Susan M. Ott, University of Washington Seattle, Washington 98195
(11a) Bisphosphonates Unusual Femur Fractures Jennifer P Schneider 2006 Geriatrics. Case Report Jennifer P. Schneider, MD, PhD, Should bisphosphonates be continued indefinitely? January 2006 Volume 61, Number 1 Geriatrics.
11b) Schneider, Jennifer P. “Bisphosphonates and low-impact femoral fractures: current evidence on alendronate-fracture risk.” Geriatrics 64.1 (2009): 18-23.Bisphosphonates Femur Fractures Jennifer P Schneider 2009 Geriatrics
(12) http://jcem.endojournals.org/cgi/content/full/90/3/1294 Odvina, Clarita V., et al. “Severely suppressed bone turnover: a potential complication of alendronate therapy.” The Journal of Clinical Endocrinology & Metabolism 90.3 (2005): 1294-1301.
Int J Oral Maxillofac Surg. 2006 Jul;35(7):588-93. Epub 2006 May 9.
Bisphosphonate-induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. Dimitrakopoulos I, Magopoulos C, Karakasis D.
Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, Greece.
(14) Reviews Nature Reviews Drug Discovery 5, 785-799 (September 2006) Targeting proteases: successes, failures and future prospects Boris Turk Cathepsin K and osteoporosis. Cathepsin K is a lysosomal cysteine cathepsin predominantly located in osteoclasts and is the major enzyme involved in bone resorption. The first evidence for this role came from a genetic study on pycnodysostosis, a rare genetic disorder associated with severe defects in bone growth, which revealed that an inactivating mutation in the gene encoding cathepsin K is a causative factor.(15) http://www.perque.com/
Russell Jaffe MD Perque Supplements
(16) Bisphosphonates for Osteoporosis, A Closer Look at the Data by Jeffrey Dach MD
A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures
Rachelle Buchbinder, Ph.D., Richard H. Osborne, Ph.D., Peter R. Ebeling, M.D., John D. Wark, Ph.D., Peter Mitchell, M.Med., Chris Wriedt, M.B., B.S., Stephen Graves, D. Phil., Margaret P. Staples, Ph.D., and Bridie Murphy, B.Sc.
N Engl J Med 2009; 361:557-568 August 6, 2009
Conclusions We found no beneficial effect of vertebroplasty as compared with a sham procedure in patients with painful osteoporotic vertebral fractures, at 1 week or at 1, 3, or 6 months after treatment. (Australian New Zealand Clinical Trials Registry number,
A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures
David F. Kallmes, M.D., Bryan A. Comstock, M.S., Patrick J. Heagerty, Ph.D., Judith A. Turner, Ph.D., David J. Wilson, F.R.C.R., Terry H. Diamond, F.R.A.C.P., Richard Edwards, F.R.C.R., Leigh A. Gray, M.S., Lydia Stout, B.S., Sara Owen, M.Sc., William Hollingworth, Ph.D., Basavaraj Ghdoke, M.D., Deborah J. Annesley-Williams, F.R.C.R., Stuart H. Ralston, F.R.C.P., and Jeffrey G. Jarvik, M.D., M.P.H. N Engl J Med 2009; 361:569-579August 6, 2009
Conclusions Improvements in pain and pain-related disability associated with osteoporotic compression fractures in patients treated with vertebroplasty were similar to the improvements in a control group.
19) Lenart, B. A., et al. “Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study.” Osteoporosis International 20.8 (2009): 1353-1362. B. A. Lenart, Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021, USA. Weill Medical College, Cornell University, New York, NY, USA;
20) Lenart, Brett A., Dean G. Lorich, and Joseph M. Lane. “Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate.” New England Journal of Medicine 358.12 (2008): 1304-1306. Brett A. Lenart, B.S. Dean G. Lorich, M.D. Joseph M. Lane, M.D. Weill Cornell Medical College New York, NY 10021
21) Capeci, Craig M., and Nirmal C. Tejwani. “Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy.” The Journal of Bone & Joint Surgery 91.11 (2009): 2556-2561.
NYU Langone Medical Center Craig Capeci, MD Specialty: Sports Medicine Phone: 212-348-3636
22) Odvina, Clarita V., et al. “Unusual mid‐shaft fractures during long‐term bisphosphonate therapy.” Clinical endocrinology 72.2 (2010): 161-168.
Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8885, USA.
23) Kwek, Ernest Beng Kee, et al. “An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy?.” Injury 39.2 (2008): 224-231.
24) Goh, S-K., et al. “Subtrochanteric insufficiency fractures in patients on alendronate therapy A CAUTION.” Journal of Bone & Joint Surgery, British Volume 89.3 (2007): 349-353.
25) Neviaser, Andrew S., et al. “Low-energy femoral shaft fractures associated with alendronate use.” Journal of orthopaedic trauma 22.5 (2008): 346-350.
26) Abrahamsen, Bo, Pia Eiken, and Richard Eastell. “Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register‐based national cohort study.” Journal of Bone and Mineral Research 24.6 (2009): 1095-1102.
27) Black, Dennis M., et al. “Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur.” New England Journal of Medicine 362.19 (2010): 1761-1771.
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