Chapter 18 References

1.        This press release by Merck got the bone density debate going. It promoted a study comparing FOSAMAX® with Actonel. It claimed that Fosamax was better, demonstrating increases in bone mineral density and reductions in markers of bone turnover. Merck Press Release, Whitehouse Station N.J., Sept. 28, 2004

2.        The popular press comments on the ensuing debate that the x-rays showing an increase in bone density do not reflect stronger bones. Martinez, B. What women can learn from debate over two leading osteoporosis drugs. Wall Street Journal Sept 28, 2004, D1.

3.        Researchers point out that the use of bisphosphonates for bones was an “accidental” discovery, not a discovery based on sound science relating to bone metabolism. Mundy GR. Directions of drug discovery in osteoporosis. Annu Rev Med. 2002;53:337-54.

4.        The mechanism of action of bone drugs are only becoming clear ten years after being in use. Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem. 2004 Sep;4(7):711-9. Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.

5.        This was the first research to show bisphosphonates kill osteoclasts by interfering with energy production. This research was funded by the makers of Actonel. Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42.

6.        These drugs are attracted into bone, where they wedge in and around bone cells. Fleisch HA. Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med. 1997 Feb;29(1):55-62.

7.        Once in bone, the drugs are there forever, as there is no enzyme that can break them down. Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG. Clinical pharmacology of alendronate sodium. Osteoporos Int. 1993;3 Suppl 3:S13-6. Merck Research Laboratories, Rahway, New Jersey 07065-0914.

8.        This animal study shows that bone drugs create disorganized bone matrix, even though an x-ray picture looks like increased bone density. Sama AA, Khan SN, Myers ER, Huang RC, Cammisa FP Jr, Sandhu HS, Lane JM. High-dose alendronate uncouples osteoclast and osteoblast function: a study in a rat spine pseudarthrosis model. Clin Orthop. 2004 Aug;(425):135-42.

9.        This detailed analysis of bone following bone drugs showed disorganized bone at doses similar to human intake and deleterious effects on bone at higher doses. Day JS, Ding M, Bednarz P, van der Linden JC, Mashiba T, Hirano T, Johnston CC, Burr DB, Hvid I, Sumner DR, Weinans H. Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties. J Orthop Res. 2004 May;22(3):465-71.

10.      Dead jaw bone is noted to occur from high-dose bisphosphonate injections. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg. 2004 May;62(5):527-534.

11.      US Food and Drug Administration. Medwatch 2004 safety alert. Zometa (zoledronic acid) injection.

12.      Merck is sued in Florida court for failure to warn patients of the risk developing osteonecrosis (dead jaw bone), which is now showing up in patients taking the oral drugs, especially when they have been on there for a longer period of time (6-7 years). Carreyrou, John Fosamax Drug Could Become Next Merck Woe. Wall Street Journal 4/12/2006; Page B1

Three reports in the literature warn of these jaw problems:

13.      Robinson NA, Yeo JF. Bisphosphonates—a word of caution. Ann Acad Med Singapore 2004 Jul;33(4 Suppl):48-9.

14.      Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws. Aust Prescriber 2004; 27: 32-33.

15.      Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med J Aust. 2005 Apr 18;182(8):417-8.

Earlier reports indicate this can happen from oral intake of Fosamax and Actonel:

16.      Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21: 4253-4254.

17.      Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62: 391-392.

Japanese researchers have been warning for over a decade on the jaw bone problem, especially in conjunction with gram negative bacterial infections in the mouth. And they have been warning of the general inflammatory nature of these drugs. The FDA does nothing to warn the American public:

18.      Funayama H, Mayanagi H, Takada H, Endo Y. Elevation of histidine decarboxylase activity in the mandible of mice by Prevotella intermedia lipopolysaccharide and its augmentation by an aminobisphosphonate. Arch Oral Biol. 2000 Sep;45(9):787-95.

19.      Endo Y, Nakamura M, Kikuchi T, Shinoda H, Takeda Y, Nitta Y, Kumagai K. Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo. Calcif Tissue Int. 1993 Mar;52(3):248-54.

20.      Sugawara S, Shibazaki M, Takada H, Kosugi H, Endo Y. Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor alpha in mice. Br J Pharmacol. 1998 Oct;125(4):735-40.

21.      Endo Y, Shibazaki M, Yamaguchi K, Nakamura M, Kosugi H. Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate. Br J Pharmacol. 1999 Feb;126(4):903-10.

22.      Yamaguchi K, Motegi K, Iwakura Y, Endo Y. Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice. Br J Pharmacol. 2000 Aug;130(7):1646-54.

Research shows the bisphosphonate drugs can activate inflammatory processes that cause plaque build-up in the arteries and may even cause plaque to rupture, serious cardiovascular risks. The FDA does not warn:

23.      Pietschmann P, Stohlawetz P, Brosch S, Steiner G, Smolen JS, Peterlik M. The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells. Calcif Tissue Int. 1998 Oct;63(4):325-30.

24.      Shimshi M, Abe E, Fisher EA, Zaidi M, Fallon JT. Bisphosphonates induce inflammation and rupture of atherosclerotic plaques in apolipoprotein-E null mice. Biochem Biophys Res Commun. 2005 Mar 18;328(3):790-3.

There are several hundred studies that indicate bisphosphonates damage the lining of the digestive tract, both by direct contact toxicity and secondary inflammation generated by the drugs.

25.      Abraham SC, Cruz-Correa M, Lee LA, Yardley JH, Wu TT. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol. 1999 Dec;12(12):1152-7.

26.      Toth E, Fork FT, Lindelow K, Lindstrom E, Verbaan H, Veress B. Alendronate-induced severe esophagitis. A rare and severe reversible side-effect illustrated by three case reports. Lakartidningen. 1998 Aug 26;95(35):3676-80.

27.      Ryan JM, Kelsey P, Ryan BM, Mueller PR. Alendronate-induced esophagitis: case report of a recently recognized form of severe esophagitis with esophageal stricture—radiographic features. Radiology. 1998 Feb;206(2):389-91.

28.      Sewell K, Schein JR. Osteoporosis therapies for rheumatoid arthritis patients: minimizing gastrointestinal side effects. Semin Arthritis Rheum. 2001 Feb;30(4):288-97.

Bisphosphonates may cause multiple other types of inflammation, depending on the susceptibility of any person:

29.      Salmen S, Berrueta L, Sanchez N, Montes H, Borges L. Nongranulomatous anterior uveitis associated with alendronate therapy. Invest Clin. 2002 Mar;43(1):49-52.

30.      Carrere C, Duval JL, Godard B, De Jaureguiberry JP, Ciribilli JM. Severe acute hepatitis induced by alendronate. Gastroenterol Clin Biol. 2002 Feb;26(2):179-80.

31.      Cadario B Alendronate: suspected pancreatitis. CMAJ 2002 Jan 8;166(1):86-7, 91-2.

32.      Gerster JH. Acute polyarthritis related to once-weekly alendronate in a woman with osteoporosis. J Rheumatol. 2004 Apr;31(4):829-30.

33.      Maclsaac RJ, Seeman E, Jerums G. Seizures after alendronate. J R Soc Med. 2002 Dec;95(12):615-6.

34.      High WA, Cohen JB, Wetherington W, Cockerell CJ. Superficial gyrate erythema as a cutaneous reaction to alendronate for osteoporosis. J Am Acad Dermatol. 2003 Jun;48(6):945-6.

35.      Phillips E, Knowles S, Weber E, Shear NH. Skin reactions associated with bisphosphonates: a report of 3 cases and an approach to management. J Allergy Clin Immunol. 1998 Oct;102(4 Pt 1):697-8.

New science shows that inflammation in bone is the true cause of bone loss. A stunning finding that is not reported in the media or known by doctors.

36.      Matsuo K, Ray N. Osteoclasts, mononuclear phagocytes, and c-Fos: new insight into osteoimmunology. Keio J Med. 2004 Jun;53(2):78-84.

37.      Takayanagi H. Inflammatory bone destruction and osteoimmunology. J Periodontal Res. 2005 Aug;40(4):287-93.

38.      Jones KB, Mollano AV, Morcuende JA, Cooper RR, Saltzman CL. Bone and brain: a review of neural, hormonal, and musculoskeletal connections. Iowa Orthop J. 2004;24:123-32.

39.      Takayanagi H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med. 2005 Jan 26.

By regulating the gene signals involved with the excessive bone inflammation (NF kappaB and TNFa), bone loss is prevented.

40.      Granchi D, Amato I, Battistelli L, Avnet S, Capaccioli S, Papucci L, Donnini M, Pellacani A, Brandi ML, Giunti A, Baldini N. In vitro blockade of receptor activator of nuclear factor-kappaB ligand prevents osteoclastogenesis induced by neuroblastoma cells. Int J Cancer. 2004 Oct 10;111(6):829-38.

41.      Jimi E, Aoki K, Saito H, D’Acquisto F, May MJ, Nakamura I, Sudo T, Kojima T, Okamoto F, Fukushima H, Okabe K, Ohya K, Ghosh S. Selective inhibition of NF-kappa B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med. 2004 Jun;10(6):617-24. Epub 2004 May 23.

42.      Involvement of iNOS-dependent NO production in the stimulation of osteoclast survival by TNF-alpha. Exp Cell Res. 2004 Aug 15;298(2):359-68.

The importance of proper rhythms and function of the hormone leptin is found essential to normal bone metabolism. Thus, the great importance of eating in harmony with the hormone leptin, as explained in my book Mastering Leptin. Healthy pregnancy may have a significant impact on the child’s later bone density.

43.      Hess R, Pino AM, Rios S, Fernandez M, Rodriguez JP. High affinity leptin receptors are present in human mesenchymal stem cells (MSCs) derived from control and osteoporotic donors. J Cell Biochem. 2005 Jan 1;94(1):50-7.

44.      De Souza MI, Williams NI. Beyond hypoestrogenism in amenorrheic athletes: energy deficiency as a contributing factor for bone loss. Curr Sports Med Rep. 2005 Feb;4(1):38-44.

45.      Takeda S. Leptin and beta-blockers in bone metabolism. Clin Calcium. 2004 Feb;14(2):241-7.

46.      Albala C, Yanez M, Devoto E, Sostin C, Zeballos L, Santos JL. Obesity as a protective factor for postmenopausal osteoporosis. Int J Obes Relat Metab Disord. 1996 Nov;20(11):1027-32.

47.      Hogan SL. The effects of weight loss on calcium and bone. Crit Care Nurs Q. 2005 Jul-Sep;28(3):269-75.

48.      Javaid MK, Godfrey KM, Taylor P, Robinson SM, Crozier SR, Dennison EM, Robinson JS, Breier BR, Arden NK, Cooper C. Umbilical Cord Leptin Predicts Neonatal Bone Mass. Calcif Tissue Int. 2005 May 5

The new science supporting bone health indicates the need for vibrant fitness between osteoblasts and osteoclasts, a process interfered with by Fosamax and Actonel. The bone drugs actually cause micro-damage in the bone to accumulate the longer they are used, resulting in abnormal bone.

49.      De Baat P, Heijboer MP, de Baat C. Development, physiology, and cell-activity of bone. Ned Tijdschr Tandheelkd 2005 Jul;112(7):258-63.

50.      Li J, Mashiba T, Burr DB. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int. 2001 Nov;69(5):281-6.

51.      Mashiba T, Mori S, Burr DB, Komatsubara S, Cao Y, Manabe T, Norimatsu H. The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab. 2005;23 Suppl:36-42.

52.      Cummings SR. How drugs decrease fracture risk: lessons from trials. J Musculoskelet Neuronal Interact. 2002 Mar;2(3):198-200.

53.      Even testing bone drugs in young people, to help perform better without stress fractures, is a failure (the drugs don’t build healthy bone). Milgrom C, Finestone A, Novack V, Pereg D, Goldich Y, Kreiss Y, Zimlichman E, Kaufman S, Liebergall M, Burr D. The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits. Bone 2004 Aug;35(2):418-24.

A variety of nutrients are now proven to support the natural function of bone-regulating inflammatory gene signals. These nutrients should not be considered a “cure” or “treatment.” They are simply evidence that many natural factors commonly found in the diet support optimal bone function and regeneration, opening the scientific door to understand how to support healthier bone function for a longer period of time.

54.      Bharti AC, Takada Y, Aggarwal BB. Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J Immunol. 2004 May 15;172(10):5940-7.

55.      Wattel A, Kamel S, Prouillet C, Petit JP, Lorget F, Offord E, Brazier M. Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NF kappa B and AP-1. J Cell Biochem. 2004 May 15;92(2):285-95.

56.      Woo JT, Nakagawa H, Notoya M, Yonezawa T, Udagawa N, Lee IS, Ohnishi M, Hagiwara H, Nagai K. Quercetin suppresses bone resorption by inhibiting the differentiation and activation of osteoclasts. Biol Pharm Bull. 2004 Apr;27(4):504-9.

57.      Rassi CM, Lieberherr M, Chaumaz G, Pointillart A, Cournot G. Modulation of osteoclastogenesis in porcine bone marrow cultures by quercetin and rutin. Cell Tissue Res. 2005 Mar;319(3):383-93. Epub 2005 Feb 2.

58.      Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Galvez J, Zarzuelo A. In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol. 2005 Feb;35(2):584-92.

59.      Wattel A, Kamel S, Mentaverri R, Lorget F, Prouillet C, Petit JP, Fardelonne P, Brazier M. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption. Biochem Pharmacol. 2003 Jan 1;65(1):35-42.

60.      Prouillet C, Maziere JC, Maziere C, Wattel A, Brazier M, Kamel S. Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway. Biochem Pharmacol. 2004 Apr 1;67(7):1307-13.

A unique form of vitamin E, tocotrienols, supports healthy bone metabolism. Regular vitamin E, d alpha tocopherol, does not help.

61.      Ima-Nirwana S, Suhaniza S. Effects of tocopherols and tocotrienols on body composition and bone calcium content in adrenalectomized rats replaced with dexamethasone. J Med Food 2004 Spring;7(1):45-51.

62.      Norazlina M, Ima-Nirwana S, Abul Gapor MT, Abdul Kadir Khalid B. Tocotrienols are needed for normal bone calcification in growing female rats. Asia Pac J Clin Nutr. 2002;11(3):194-9.

63.      Theriault A, Chao JT, Gapor A, Chao JT, Gapor A. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Gapor Abdul. Atherosclerosis 2002 Jan;160(1):21-30.

64.      Gu JY, Wakizono Y, Sunada Y, Hung P, Nonaka M, Sugano M, Yamada K. Dietary effect of tocopherols and tocotrienols on the immune function of spleen and mesenteric lymph node lymphocytes in Brown Norway rats. Biosci Biotechnol Biochem. 1999 Oct;63(10):1697-702.

The vital importance of magnesium for bone health is now understood in the context of helping to regulate bone gene signals.

65.      Stendig-Lindberg G, Koeller W, Bauer A, Rob PM. Experimentally induced prolonged magnesium deficiency causes osteoporosis in the rat. Eur J Intern Med. 2004 Apr;15(2):97-107.

66.      Rude RK, Gruber HE, Norton HJ, Wei LY, Frausto A, Mills BG. Bone loss induced by dietary magnesium reduction to 10% of the nutrient requirement in rats is associated with increased release of substance P and tumor necrosis factor-alpha. J Nutr. 2004 Jan;134(1):79-85.

67.      Rude RK, Gruber HE, Wei LY, Frausto A, Mills BG. Magnesium deficiency: effect on bone and mineral metabolism in the mouse. Calcif Tissue Int. 2003 Jan;72(1):32-41. Epub 2002 Oct 10.

The importance of essential fatty acids, especially DHA, to bone health is identified. This is a significant finding for women following menopause, as DHA helps bones compensate for the natural drop in estrogen during this time of life.

68.      Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH, Fitzgerald KA, Hwang DH. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004 Apr 23;279(17):16971-9. Epub 2004 Feb 13.

69.      Reinwald S, Li Y, Moriguchi T, Salem N Jr, Watkins BA. Repletion with (n-3) fatty acids reverses bone structural deficits in (n-3)-deficient rats. J Nutr. 2004 Feb;134(2):388-94.

70.      Sun D, Krishnan A, Zaman K, Lawrence R, Bhattacharya A, Fernandes G. Dietary n-3 fatty acids decrease osteoclastogenesis and loss of bone mass in ovariectomized mice. J Bone Miner Res. 2003 Jul;18(7):1206-16.

71.  Sun L, Tamaki H, Ishimaru T, Teruya T, Ohta Y, Katsuyama N, Chinen I. Inhibition of osteoporosis due to restricted food intake by the fish oils DHA and EPA and perilla oil in the rat. Biosci Biotechnol Biochem. 2004 Dec;68(12):2613-5.