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Dr. Karpf’s Response to Bone Drugs Article

Dr. Karpf’s Response to Bone Drugs Article

Original Article: Questions About Bone Drugs Persist Despite Media Hype

By Martha Rosenberg

Epoch Times July 19, 2018 6:18 pm Last Updated: July 20, 2018 11:38 am

There is an old saying that if you keep going into a barber shop, eventually you will get a haircut. The same can be said of Pharma’s many health “screenings.”

The suggestions to get screenings for depression, “osteopenia” or even exocrine pancreatic insufficiency (EPI) are meant to sound like they come from public health programs. Some are even given public service announcement status, running on media for free. But they are what is now called “disease mongering”––selling a disease and the fear of the disease to find new patients to take expensive drugs. The ad industry calls them “unbranded” advertising because they never mention the drug they are pushing––just the disease they want you to fear. So you’ll get the haircut.

Depression screening, for example, is seldom if ever pushed and financed by anyone but Pharma; the now-defunct TeenScreen to find early signs of depression in young people had “ties to the pharmaceutical industry,” the Scientific American confirmed. PSA blood tests also over-screen reports Cancer Research UK finding cancers that “that if left undetected wouldn’t cause harm.” Americans are shamelessly over-screened, over-diagnosed, over-treated and overmedicated and it is done for no other reason than to make money off them.

This week the New York Times does some heavy lifting for Pharma screening and drugs. “Ladies…consider getting your bone density checked,” Jane Brody writes in its Science section. There is “solid evidence that treatment with a bone-preserving or bone-building drug is beneficial when a bone density test reveals a level of bone loss defined as osteoporosis in the spine or a hip.” Pharma thanks her.

The problem is Brody omits three crucial facts that people should know before they submit to bone scans.

  • Bone density machines were dreamed up, placed in doctors’ offices and the scans made Medicare reimbursableby Merck to sell its bone drug Fosamax. The scheme worked. By 1999, there were between 8,000 and 10,000 bone scan machines in medical offices, when there had been only 750 before Merck’s machinations.

Dr. Karpf’s Response

This is a blatant falsehood.  If you state that Merck worked to make bone density machines more readily available, as did P&G and other companies, to help diagnose osteoporosis, this is true.  But Merck did not “dream up” bone density machines.  In 1963, John Cameron and James Sorenson introduced single photon absorptiometry (SPA) to measure peripheral bone mineral density (Cameron JR and Sorenson J, Measurement of bone mineral in vivo: an improved method, Science 143: p230, 1963). 

In 1965 came the addition of a dual energy source for measuring regions of interest that could not be easily submerged in or surrounded by water. However, dual photon absorptiometry (DPA) was not employed until the 1980s when clinical applications became relevant.  Gadolinium (153Gd), which emits two distinct energies, became available in the 1970s and was used in the first commercially introduced DPA units.  At that time, Lunar made DPA commercially available for the measurement of spine and hip bone BMD, along with total body composition (bone mineral, fat and fat-free mass) (Mazess RB, Peppler WW, Harrison JE et al, Total body bone mineral and lean body mass by dual photon absorptiometry, Calcif Tissue Int 33: p365, 1981). 

Resolution limits, degrading energy source and long scan times (20 to 40 minutes) led to the transition from DPA – with its 153Gd source – to dual-energy x-ray absorptiometry (Wahner HW, Dunn WL, Brown ML, et al. Comparison of dual-energy x-ray absorptiometry and dual phone absorptiometry for bone mineral measurements of the lumbar spine, Mayo Clinic Proc 63: pp1,075-1,084, 1988).

Hologic Inc introduced DXA commercially in 1987, two years before Merck even licensed alendronic acid from Gentili and four years before the start of the 3-year pivotal Phase 3 trials of Fosamax (alendronate sodium) that supported its registration in 4Q 1995.

“Osteopenia,” which drives so many drug sales, was never meant to be “a disease in itself to be treated,” says Dartmouth Medical School professor Anna Tosteson, MD who attended the 1992 World Health Organization meeting where the term was invented. The scientists in the room hastily agreed on the term because they wanted to adjourn, she says. The bone density units, called “T scores,” used to define “osteopenia” are equally fallacious, wrote Susan Kelleher in Seattle Times: They have “boundaries so broad they include more than half of all women over 50.”

Dr. Karpf’s Response: 

As an international osteoporosis expert I have been a long time supporter (often quite vociferously) of Anna Tosteson’s position that “osteopenia” is NOT a disease.  But Susan Kelleher’s argument, and yours by proxy, is not cogent. 

The reason why “osteoporosis” (which is technically defined as an increased risk of osteoporotic fracture) should not be diagnosed simply as anyone who has T-score ≤-2.5 is not because this T-score cut-off diagnoses about 40-50% of women older than 50 who will have a fracture of the spine, hip or wrist in their lifetime.  Rather, the main issue is that while using a T-score cut-off diagnoses the right NUMBER of women, it does not always diagnose the right women. 

As far back as 1995, we knew that only 1/3 of the post-menopausal women who have a fracture of the spine, hip or wrist have T-score diagnosis lower than -2.5; in fact, 2/3 of women who fracture have T-scores that are better than -2.5. 

This observation was the basis for development of the FRAX calculation by Dr. John Kanis and others, which uses Femoral Neck BMD value as well as other important clinical risk factors such as age, steroid treatment, rheumatoid arthritis, prior osteoporotic fractures and parental history of hip fracture to calculate a 10-year risk for major and hip fractures.

Brody omits that questions about the efficacy of bisphosphonate drugs (the drugs she is pushing) preceded their aggressive marketing and were later confirmed in users as spontaneous fractures surfaced. As early as 2004, Gordon Strewler, MD, in the New England Journal of Medicine, and Susan M. Ott, MD, in the Annals of Internal Medicine, warned that the actions of bisphosphonates could paradoxically make bones brittle and cause fractures because they stop bone renewal. Reports in the Journal of Clinical Endocrinology & MetabolismJournal of Orthopaedic Trauma, and Injury followed. And in 2008, Phuli Cohan, MD, appeared on CBS TV in Boston with x-rays of a woman whose hip had shattered after years on Fosamax. “There is actually bone death occurring,” said Cohan. His worst fears— “that we’d be seeing spontaneous fractures”—were realized.

Dr. Karpf’s Response: 

You unethically cite references to support your position.  Buck (Gorden) Strewler’s article in the NEJM (“Decimal Point — Osteoporosis Therapy at the 10-Year Mark.  NEJM 350;12, March 18, 2004) states:  

“Alendronate was the first orally active bisphosphonate introduced in the United States for the treatment of osteoporosis.  In initial clinical trials, alendronate increased bone mineral density, decreased bone turnover, and reduced the risk of vertebral and hip fracture in postmenopausal women with osteoporosis.  Follow-up studies have confirmed that the benefits of alendronate are maintained through seven years of therapy. 

In this issue of the NEJM, Bone et al. (pages 1189–1199) report on 10 years of experience with alendronate, an extension of the original 3-year randomized, controlled trials.  Two groups of postmenopausal women received alendronate at a dose of 5 mg or 10 mg daily.  Bone turnover, as measured by means of markers of bone formation and bone resorption, was reduced by more than 50 percent in women who received continuous alendronate therapy.  Bone mineral density at the lumbar spine continued to increase throughout the 10-year period in both alendronate groups and was stable at other skeletal sites.  A third group (the discontinuation group), who had initially received a 20 mg dose, was switched to 5 mg for years 3 through 5 and then to placebo for years 6 through 10.  In this group, a small increase in bone turnover in years 6 through 10 was accompanied by a decrease in bone mineral density at most skeletal sites. 

The groups were too small to permit the detection of influences of treatment on the rate of fractures.  High bone turnover increases the risk of fracture, perhaps because of the harmful effects of rapid resorption on the microarchitecture of bone, such as the perforation of trabecular plates.  Antiresorptive agents reduce fracture rates in part by reducing bone turnover rates. 

In short-term studies of antiresorptive therapy, the reduction in bone turnover explains more of the treatment-related reduction in the risk of fracture than does the increase in bone mineral density.  The study of Bone et al. provides convincing evidence that the biochemical effects of alendronate on bone turnover remain stable over the course of 10 years of therapy, without any progression of its antiresorptive action or noticeable increase in the incidence of fractures.” 

And then the article concludes “Although 10 years of alendronate treatment appears to be safe, the optimal duration of treatment has not been established.” 

These are all accurate statements, as Fosamax was approved on the basis of long-term nonclinical studies in 5 species (lifetime in mice and rats, 2-3 years in dogs, mini-pigs and monkeys) that demonstrated normal bone quality and improved bone strength, and the two phase 3 clinical trials and the 4.25-year FIT trial that demonstrated normalization of bone turnover, increase in BMD of the spine, hip and total body, and significant reductions in the incidence of fractures of the spine and hip.

In contrast to Dr. Strewler, who is a brilliant endocrinologist who has done primary research in metabolic bone disease, Dr. Cohan (who you cite) is an ER physician who specializing in Eastern medicine and lacks any experience in osteoporosis or metabolic bone disease. 

In fact, when FDA required the manufacturers of Fosamax, Actonel, Boniva, and Reclast to search their entire Phase 2, Phase 3 and Phase 4 Randomized Controlled Trial databases (randomized, database studies of 2-10 years in duration amounting to almost 100,000 patient-years of experience) for atypical femoral fractures (AFFs), there was a small number (like 2) in the bisphosphonate arm and an equal number in the placebo arm. 

In the large FIT trial, which included over 27,000 patient-years of experience, there was not a single AFF in either the active or the placebo group.  So what might account for the rare report of AFF in patients treated with bisphosphonates in case-control studies but not in huge RCTs?  Several possible explanations:

  • These trials primarily enrolled women with osteoporosis (who are at increased fracture risk); whereas in the “real world” many women are treated for “osteopenia” who do not have increased fracture risk (as I stated above, I agree with you and Dr. Tosteson that “osteopenia” should not be a diagnosis in any woman < 65 years of age, consistent with the population in the Study of Osteoporotic Fractures. Osteopenia should not even be a diagnosis in a 65-year woman who was on estrogen from menopause at age 50 until age 65.)
  • These trials excluded patients who might have hypophosphatasia. In contrast, the average physician who sees a 50-year-old woman who has low BMD and may have had a stress fracture of a metatarsal or femoral neck and whose total alkaline phosphatase value is < 40 is routinely diagnosed with “osteoporosis” and treated with a bisphosphonate, which is contra-indicated in patients with hypophosphatasia.
  • Typically, experts will check bone turnover markers and recommend anabolic therapies (eg, Tymlos or Forteo) for the approximately 5% of people with osteoporosis who have LOW bone turnover, as opposed to the much more common INCREASED bone turnover. The average physician never checks bone turnover markers, or if they do don’t understand them, and so uses anti-resorptive therapies in patients who cannot benefit from a further reduction in their rate of bone turnover.

Finally, Brody omits the role of the Western diet and Western drugs in bone loss. “There is growing evidence that consumption of a Western diet is a risk factor for osteoporosis through excess acid supply,” says an article in the Proceedings of the Nutrition Society, a theory also advanced by heart expert Dean Ornish, MD, of the Preventive Medicine Research Institute.”

“Elderly women with a high dietary ratio of animal to vegetable protein intake have more rapid femoral neck bone loss and a greater risk of hip fracture than do those with a low ratio,” says an article in the American Journal of Clinical Nutrition.

Dr. Karpf’s Response: 

This is bogus science.  Many folks who push “the alkaline diet” simply want to sell cookbooks and supplements.  While there are valid reasons why the Western Diet (which is high in “acidic” foods like meat and low in “alkaline” foods like fruits and vegetables) is unhealthy, it has NOTHING to do with acidification. 

A little physiology: Human blood is slightly alkaline, with a pH between 7.35 and 7.45.  Our stomach acid is very acidic (it makes hydrochloric acid), with a pH of ≤3.5, so it can break down food.  Food in the stomach will buffer some of this acid, but when the gastric contents enter the first portion of the duodenum they are still acidic (pH < 7.0). 

The pancreas releases, among other things, bicarbonate to buffer the acid. 

Additionally, our kidneys play a key role in acid-base balance, ensuring our blood stays in the normal pH range of 7.35-7.45 (mean 7.40). 

Unless someone drinks lots of strong acid (which would kill them by burning their oropharynx and esophagus), nothing you eat will change the pH of your blood, which is under strong homeostatic control. 

The alkaline diet claims to help your body maintain its blood pH level.  In fact, nothing you eat is going to substantially change the pH of your blood.

Popular asthma drugs, steroids, digestive drugs like Nexium and Prilosec and antidepressants also can cause “drug-induced osteoporosis,” says an article in the American Journal of Medicine. And studies in the Archives of Internal Medicine found that patients on antidepressants like Prozac, Zoloft, and Paxil had 6 percent lower bone density in their spines and 4 percent lower bone density in their hips than those not on antidepressants, reports US News & World Report. Yes, once again, Pharma says we should take a drug to treat the side effects of another drug.

Martha Rosenberg is author of the award-cited food exposé “Born With a Junk Food Deficiency,” distributed by Random House. A nationally known muckraker, she has lectured at the university and medical school level and appeared on radio and television.

Views expressed in this article are the opinions of the author and do not necessarily reflect the views of The Epoch Times.

Dr. Karpf’s Response: 

In conclusion, Jane Brody has been an experienced and much-respected science writer for the New York Times for 42 years. She received her B.S. degree in biochemistry from the New York State College of Agriculture and Life Sciences at Cornell University in 1962 and a master’s degree in science writing from the University of Wisconsin School of Journalism the following year.  Ms. Brody has honorary doctorates from several universities including Princeton.  Her specs as a science writer are impeccable. 

In contrast, you are apparently a blogger and author, with no link to your education or training.  This article reflects a very biased and slanted diatribe against “big pharma” in general, supported by very selective references (some of which are misstated) simply chosen to support your viewpoint, and does not appear to reflect ethical journalism.

David B. Karpf, MD
Adj. Clinical Professor of Endocrinology, Gerontology & Metabolism
Stanford University School of Medicine
Attending, Osteoporosis & Metabolic Bone Disease Clinic
Stanford University Hospital & Clinics
dbkarpf@stanford.edu

Co-Chair, Medical and Scientific Advisory Board
American Bone Health
www.americanboehealth.org

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