Osteoporosis: The Need for Prevention and Treatment
Karan Baucom
Lara Pizzorno
Joseph Pizzorno
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Keywords

Osteoporosis
Osteopenia
Treatment
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Abstract

Osteoporosis is a preventable, potentially crippling disease characterized by low
bone density and increased bone fragility that affects millions of people. The seeds
of this pernicious disease are sown during adolescence, when the skeleton is most
active in absorbing dietary calcium and building up nearly all the bone mass that will
carry the teenager throughout life. Dietary intake of calcium, vitamin D and vitamin
K, particularly vitamin K2, is critical during this life stage for optimal bone growth;
unfortunately, the majority of adolescents in the USA do not consume adequate
amounts. In addition, many adolescents are now using oral contraceptives or
intrauterine devices that prevent ovulation, thus inhibiting formation of progesterone
required for the development of osteoblasts. Oral contraceptives also lower blood
levels of vitamins B6 and B12, both of which are necessary to prevent elevated
levels of homocysteine, whose impact on bone can be significant. In addition to
“the pill,” many commonly prescribed medications disrupt normal bone remodeling
and promote osteoporosis. Other remediable factors that cause excessive bone
loss include insufficiencies of key nutrients, such as vitamin D3, vitamin K2, and
calcium, required for healthy bone remodeling. It is important to recognize key risk
factors and manage those that can be modified to prevent disease and/or minimize
risk of fracture. This article presents an overview of osteoporosis, pathophysiology
of disease, diagnostic tests, risk factors, and clinical recommendations for healthy
bones.

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References

National Osteoporosis Foundation (http://www.nor.org). Accessed November 1, 2013 .
Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006; 17:1726–33.
Becker DJ, Kilgore ML, Morrisey MA. The societal burden of osteoporosis. Curr Rheumatol Rep. 2010; 12:186–91.
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007; 22:465–75.
Budhia S, Mikyas Y, Tang M, Badamgarav E. Osteoporotic fractures: a systematic review of U.S. healthcare costs and resource utilization.Pharmacoeconomics. 2012; 30:147–70.
Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med. 1991; 151:2026–32.
Braithwaite RS, Col NF, Wong JB. Estimating hip fracture morbidity, mortality and costs. J Am Geriatr Soc. 2003; 51:364–70.
Dolan MM, Hawkes WG, Zimmerman SI, et al. Delirium on hospital admission in aged hip fracture patients: prediction of mortality and 2-year functional outcomes. J Gerontol A Biol Sci Med Sci. 2000; 55:M527–34.
Lenze EJ, Munin MC, Skidmore ER, et al. Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression. J Am Geriatr Soc. 2007; 55:81–6.
Munch S, Shapiro S. The silent thief: osteoporosis and women’s health care across the life span. Health Soc Work. 2006; 31:44–53.
Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. J Am Med Assoc. 2009; 301:513–21.
Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999; 353:878–82.
Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med. 1997; 103:12S–7S.
Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002; 359:1761–7.
Wiktorowicz ME, Goeree R, Papaioannou A, Adachi JD, Papadimitropoulos E. Economic implications of hip fracture: health service use, institutional care and cost in Canada. Osteoporos Int. 2001; 12:271–8.
Siris ES. Patients with hip fracture: what can be improved? Bone. 2006; 38:S8–12.
Pizzorno L, Wright JV. Your Bones, 2nd edn. Edinburgh, VA: Praktikos Books; 2013.
Rizzoli R, Brandi ML, Dreinhofer K, Thomas T, Wahl DA, Cooper C. The gaps between patient and physician understanding of the emotional and physical impact of osteoporosis. Arch Osteoporos. 2010; 5:145–53.
Satterfield T, Johnson SM, Slovic P, Neil N, Schein JR. Perceived risks and reported behaviors associated with osteoporosis and its treatment.Women Health. 2000; 31:21–40.
Curtis JR, McClure LA, Delzell E, et al. Population-based fracture risk assessment and osteoporosis treatment disparities by race and gender.J Gen Intern Med. 2009; 24:956–62.
Adler RA. Osteoporosis in men: recent progress. Endocrine. 2013; 44(1):40–6.
Adler RA, Gill RS. Clinical utility of denosumab for treatment of bone loss in men and women. Clin Interv Aging. 2011; 6:119–24.
Glüer CC, Marin F, Ringe JD, et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J Bone Miner Res. 2013; 28(6):1355–68.
Mosekilde L, Vestergaard P, Rejnmark L. The pathogenesis, treatment and prevention of osteoporosis in men. Drugs. 2013; 73(1):15–29.
Saggese G, Baroncelli GI, Bertelloni S. Osteoporosis in children and adolescents: diagnosis, risk factors, and prevention. J Pediatr Endocrinol Metab. 2001; 14:833–59.
Campion JM, Maricic MJ. Osteoporosis in men. Am Fam Physician. 2003; 67:1521–6.
Seeman E. Pathogenesis of bone fragility in women and men. Lancet. 2002; 359:1841–50.
Orwig DL, Chan J, Magaziner J. Hip fracture and its consequences: differences between men and women. Orthop Clin North Am. 2006; 37:611–22.
Fitzpatrick LA. Secondary causes of osteoporosis. Mayo Clin Proc. 2002; 77:453–68.
Heaney RP, Abrams S, Dawson-Hughes B, et al. Peak bone mass. Osteoporos Int. 2000; 11:985–1009.
Lippuner K. The future of osteoporosis treatment – a research update. Swiss Med Wkly. 2012; 142:w13624.
Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Can Med Assoc J. 2002; 167:S1–34.
Cashman KD. Vitamin D in childhood and adolescence. Postgrad Med J. 2007; 83(978):230–5.
Cashman KD. Vitamin K status may be an important determinant of childhood bone health. Nutr Rev. 2005; 63(8):284–9.
Tsugawa N, Uenishi K, Ishida H, et al. A novel method based on curvature analysis for estimating the dietary vitamin K requirement in adolescents. Clin Nutr. 2012; 31(2):255–60.
“Vitamin K: another reason to eat your greens”January 2000, Agricultural Research Magazine. (http://www.ars.usda.gov/is/ar/archive/jan00/green0100.htm?pf=1). Accessed September 13, 2013 .
Lussana FM, Zighetti ML, Bucciarelli P, et al. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res. 2003; 112(1–2):37–41.
McLean RR, Jacques PF, Selhub J, et al. Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. J Clin Endocrinol Metab. 2008; 93(6):2206–12.
Isley MM, Kaunitz AM. Update on hormonal contraception and bone density. Rev Endocr Metab Disord. 2011; 12(2):93–106.
Seifert-Klauss V, Schmidmayr M, Hobmaier E, Wimmer T. Progesterone and bone: a closer link than previously realized. Climacteric. 2012; 15(Suppl 1):26–31.
Bahamondes MV, Monteiro I, Castro S, et al. Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system. Hum Reprod. 2010; 25(5):1158–64.
Pérez-López FR, Brincat M, Erel CT, et al. EMAS position statement: vitamin D and postmenopausal health. Maturitas. 2012; 71(1):83–8.
Luz Rentero M, Carbonell C, Casillas M, et al. Risk factors for osteoporosis and fractures in postmenopausal women between 50 and 65 years of age in a primary care setting in Spain: a questionnaire. Open Rheumatol J. 2008; 2:58–63.
Bolton JM, Targownik LE, Leung S, et al. Risk of low bone mineral density associated with psychotropic medications and mental disorders in postmenopausal women. J Clin Psychopharmacol. 2011; 31(1):56–60.
Bolton JM, Metge C, Lix L, et al. Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 2008; 28(4):384–91.
Damsa C, Bumb A, Bianchi-Demicheli F, et al. “Dopamine-dependent” side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry. 2004; 65(8):1064–8.
O’Keane V. Antipsychotic-induced hyperprolactinaemia, hypogonadism and osteoporosis in the treatment of schizophrenia. J Psychopharmacol. 2008; 22(Suppl 2):70–5.
O’Keane V, Meaney AM. Antipsychotic drugs: a new risk factor for osteoporosis in young women with schizophrenia? J Clin Psychopharmacol. 2005; 25(1):26–31.
Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Can Med Assoc J. 2009; 180(1):32–9.
Dormuth CR, Carney G, Carleton B, et al. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009; 169(15):1395–402.
Douglas IJ, Evans SJ, Pocock S, et al. The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med. 2009; 6(9):e1000154.
Aubert RE, Herrera V, Chen W, et al. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010; 12(8):716–21.
Bodmer M, Meier C, Kraenzlin ME, et al. Risk of fractures with glitazones: a critical review of the evidence to date. Drug Saf. 2009; 32(7):539–47.
Bruedigam C, Eijken M, Koedam M, et al. A new concept underlying stem cell lineage skewing that explains the detrimental effects of thiazolidinediones on bone. Stem Cells. 2010; 28(5):916–27.
Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008; 9(1):28–36.
Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment.Clin J Pain. 2010; 26(5):374–80.
Colameco S. Opioid-induced endocrinopathy: diagnosis and screening. J Pain Palliat Care Pharmacother. 2012; 26:73–5.
Elliott JA, Horton E, Fibuch EE. The endocrine effects of long-term oral opioid therapy: a case report and review of the literature. Opioid Manag. 2011; 7(2):145–54.
Adler RA, Curtis JR, Saag K, et al. Glucocorticoid-induced osteoporosis. In: Marcus R, Feldman D, Nelsen DA, Rosen CJ, eds. Osteoporosis, 3rd edn. San Diego, CA: Elsevier Academic Press; 2008. pp. 1135–66.
Van Staa TP, Laan RF, Barton IP, et al. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum. 2003; 48:3224–9.
Steinbuch M, Youket TE, Cohen S. Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int. 2004; 15:323–8.
Weinstein RS. Clinical practice Glucocorticoid-induced bone disease. N Engl J Med. 2011; 365(1):62–70.
Weinstein RS. Glucocorticoid-induced osteoporosis. In: Rosen C, ed. The ASBMR Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th edn. Washington, DC: ASBMR; 2008. pp. 267–72.
Wright JV, Lenard L. Why Stomach Acid is Good for You, Natural Relief from Heartburn, Indigestion, Reflux & GERD. Lanham, MD: M. Evans; 2001. pp. 25–8.
Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM. 2010; 103(6):387–95.
http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/bone_mass.asp .
Jarvinen TL, Kannus P, Sievanen H. Estrogen and bone – a reproductive and locomotive perspective. J Bone Miner Res. 2003; 18:1921–31.
Peacock M, Koller DL, Lai D, Hui S, Foroud T, Econs MJ. Bone mineral density variation in men is influenced by sex-specific and non sex-specific quantitative trait loci. Bone. 2009; 45:443–8.
Looker AC, Melton LJ III, Harris TB, Borrud LG, Shepherd JA. Prevalence and trends in low femur bone density among older US adults: NHANES 2005–2006 compared with NHANES III. J Bone Miner Res. 2010; 25:64–71.
Robitaille J, Yoon PW, Moore CA, et al. Prevalence, family history, and prevention of reported osteoporosis in U.S. women. Am J Prev Med. 2008; 35:47–54.
http://www.gdx.net/core/one-page-test-descriptions/Osteo-Genomic-Test-Description.pdf. (Note that this profile is being discontinued but the SNPs are evaluated via other profiles available at Genova Diagnostics.)
Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004; 79:362–71.
Lips P, Hosking D, Lippuner K, et al. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med. 2006; 260:245–54.
Feskanich D, Willett WC, Colditz GA. Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women. Am J Clin Nutr. 2003; 77:504–11.
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992; 327(23):1637–42.
Meunier PJ, Chapuy MC, Arlot ME, et al. Can we stop bone loss and prevent hip fractures in the elderly? Osteoporos Int. 1994; 4(Suppl 1):71–6.
Chapuy MC, Meunier PJ. Prevention of secondary hyperparathyroidism and hip fracture in elderly women with calcium and vitamin D3 supplements. Osteoporos Int. 1996; 6(Suppl 3):60–3.
Chapuy MC, Pamphile R, Paris E, et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Osteoporos Int. 2002; 13(3):257–64.
Lilliu H, Pamphile R, Chapuy MC, et al. Calcium-vitamin D3 supplementation is cost-effective in hip fractures prevention. Maturitas. 2003; 44(4):299–305.
Chapuy MC, Arlot ME, Delmas PD, et al. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Brit Med J. 1994; 308(6936):1081–2.
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. J Am Med Assoc. 2005; 293:2257–64.
Grimnes G, Joakimsen R, Figenschau Y, Torjesen PA, Almas B, Jorde R. The effect of high-dose vitamin D on bone mineral density and bone turnover markers in postmenopausal women with low bone mass – a randomized controlled 1-year trial. Osteoporos Int. 2012; 23:201–11.
Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. J Am Med Assoc. 2004; 291:1999–2006.
http://www.vitamindcouncil.org/about-vitamin-d/testing-for-vitamin-d/. Accessed September 12, 2013 .
Mundy GR, Guise TA. Hormonal control of calcium homeostasis. Clin Chem. 1999; 45:1347–52.
Trivedi R, Mithal A, Chattopadhyay N. Anabolics in osteoporosis: the emerging therapeutic tool. Curr Mol Med. 2010; 10(1):14–28.
Brixen KT, Christensen PM, Ejersted C, et al. Teriparatide (biosynthetic human parathyroid hormone 1–34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol. 2004; 94(6):260–70.
Kim BJ, Seo M, Huh JK, et al. Associations of plasma homocysteine levels with arterial stiffness in prehypertensive individuals. Clin Exp Hypertens. 2011; 33:411–17.
LeBoff MS, Narweker R, LaCroix A, et al. Homocysteine levels and risk of hip fracture in postmenopausal women. J Clin Endocrinol Metab. 2009; 94:1207–13.
van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004; 350:2033–41.
Herrmann M, Peter SJ, Umanskaya N, et al. The role of hyperhomocysteinemia as well as folate, vitamin B6 and B12 deficiencies in osteoporosis: a systematic review. Clin Chem Lab Med. 2007; 45:1621–32.
Kuyumcu ME, Yesil Y, Ozturk ZA, et al. The association between homocysteine (hcy) and serum natural antioxidants in elderly bone mineral densitometry (BMD). Arch Gerontol Geriatr. 2012; 55:739–43.
Tucker KL, Hannan MT, Qiao N, et al. Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study. J Bone Miner Res. 2005; 20:152–58.
Maggio D, Barabani M, Pierandrei M, et al. Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab. 2003; 88:1523–7.
Gerdhem P, Ivaska KK, Isaksson A, et al. Associations between homocysteine, bone turnover, BMD, mortality, and fracture risk in elderly women. J Bone Miner Res. 2007; 22:127–34.
Zhu K, Beilby J, Dick IM, Devine A, Soos M, Prince RL. The effects of homocysteine and MTHFR genotype on hip bone loss and fracture risk in elderly women. Osteoporos Int. 2009; 20:1183–91.
Bozkurt N, Erdem M, Yilmaz E, et al. The relationship of homocyteine, B12 and folic acid with the bone mineral density of the femur and lumbar spine in Turkish postmenopausal women. Arch Gynecol Obstet. 2009; 280:381–7.
Saito M. [Biochemical markers of bone turnover. New aspect. Bone collagen metabolism: new biological markers for estimation of bone quality].Clin Calcium. 2009; 19(8):1110–7.
Petramala L, Acca M, Francucci CM, et al. Hyperhomocysteinemia: a biochemical link between bone and cardiovascular system diseases? J Endocrinol Invest. 2009; 32(Suppl 4):10–14.
Yilmaz N, Eren E. Homocysteine oxidative stress and relation to bone mineral density in post-menopausal osteoporosis. Aging Clin Exp Res. 2009; 21(4–5):353–7.
Haliloglu B, Aksungar FB, Ilter E, et al. Relationship between bone mineral density, bone turnover markers and homocysteine, folate and vitamin B12 levels in postmenopausal women. Arch Gynecol Obstet. 2010; 281(4):663–8.
Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc. 1993; 270:2693–8.
Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med. 1999; 340:1449–54.
ACOG Practice Bulletin N. 129. Osteoporosis. Obstet Gynecol. 2012; 120:718–34.
Seifert-Klauss V, Prior JC. Progesterone and bone: actions promoting bone health in women. J Osteoporos. 2010; 2010:845180.
Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010; 31:266–300.
Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis. 2002; 8(3):147–59.
Lange U, Teichmann J, Schett G, et al. [Osteoimmunology: how inflammation influences bone metabolism]. Dtsch Med Wochenschr. 2013; 138(37):1845–9 (in German) .
Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. J Am Med Assoc. 2003; 290:1729–38.
Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women’s Health Initiative randomized trial. J Bone Miner Res. 2006; 21:817–28.
Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009; 121(1):73–85.
Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008; 29:441–64.
Mellstrom D, Vandenput L, Mallmin H, et al. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res. 2008; 23:1552–60.
Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C. Androgens and bone. Endocr Rev. 2004; 25:389–425.
Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 1997; 82:2386–90.
Crawford BA, Liu PY, Kean MT, Bleasel JF, Handelsman DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab. 2003; 88:3167–76.
Jones G, Scott FS. A cross-sectional study of smoking and bone mineral density in premenopausal parous women: effect of body mass index, breastfeeding, and sports participation. J Bone Miner Res. 1999; 14:1628–33.
Hollenbach KA, Barrett-Connor E, Edelstein SL, Holbrook T. Cigarette smoking and bone mineral density in older men and women. Am J Public Health. 1993; 83:1265–70.
Holmberg T, Bech M, Curtis T, Juel K, Gronbaek M, Brixen K. Association between passive smoking in adulthood and phalangeal bone mineral density: results from the KRAM study – the Danish Health Examination Survey 2007–2008. Osteoporos Int. 2011; 22:2989–99.
Ward KD, Klesges RC. A meta-analysis of the effects of cigarette smoking on bone mineral density. Calcif Tissue Int. 2001; 68:259–70.
Krall EA, Dawson-Hughes B. Smoking increases bone loss and decreases intestinal calcium absorption. J Bone Miner Res. 1999; 14:215–20.
Rapuri PB, Gallagher JC, Balhorn KE, Ryschon KL. Smoking and bone metabolism in elderly women. Bone. 2000; 27:429–36.
Michnovicz JJ, Hershcopf RJ, Haley NJ, Bradlow HL, Fishman J. Cigarette smoking alters hepatic estrogen metabolism in men: implications for atherosclerosis. Metabolism. 1989; 38:537–41.
Barbieri RL, Gochberg J, Ryan KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. J Clin Invest. 1986; 77:1727–33.
Cassidenti DL, Vijod AG, Vijod MA, Stanczyk FZ, Lobo RA. Short-term effects of smoking on the pharmacokinetic profiles of micronized estradiol in postmenopausal women. Am J Obstet Gynecol. 1990; 163:1953–60.
Tang TH, Fitzsimmons TR, Bartold PM. Effect of smoking on concentrations of receptor activator of nuclear factor kappa B ligand and osteoprotegerin in human gingival crevicular fluid. J Clin Periodontol. 2009; 36:713–18.
Lappin DF, Sherrabeh S, Jenkins WM, Macpherson LM. Effect of smoking on serum RANKL and OPG in sex, age and clinically matched supportive-therapy periodontitis patients. J Clin Periodontol. 2007; 34:271–7.
Sorensen LT, Toft BG, Rygaard J, et al. Effect of smoking, smoking cessation, and nicotine patch on wound dimension, vitamin C, and systemic markers of collagen metabolism. Surgery. 2010; 148:982–90.
Ma L, Zheng LW, Sham MH, Cheung LK. Uncoupled angiogenesis and osteogenesis in nicotine-compromised bone healing. J Bone Miner Res. 2010; 25:1305–13.
Kazantzis G. Cadmium, osteoporosis and calcium metabolism. Biometals. 2004; 17(5):493–8.
Rothem DE, Rothem L, Soudry M, et al. Nicotine modulates bone metabolism-associated gene expression in osteoblast cells. J Bone Miner Metab. 2009; 27(5):555–61.
Kamer AR, El-Ghorab N, Marzec N, et al. Nicotine induced proliferation and cytokine release in osteoblastic cells. Int J Mol Med. 2006; 17(1):121–7.
Op. cit., Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009; 121(1):73–85.
International Society for Clinical Densitometry (http://www.iscd.org) .
Cauley JA, Hochberg MC, Lui LY, et al. Long-term risk of incident vertebral fractures. J Am Med Assoc. 2007; 298:2761–7.
Lafleur J, McAdam-Marx C, Kirkness C, Brixner DI. Clinical risk factors for fracture in postmenopausal osteoporotic women: a review of the recent literature. Ann Pharmacother. 2008; 42:375–86.
Huber F, Traber L, Roth HJ, et al. Markers of bone resorption – measurement in serum, plasma or urine? Clin Lab. 2003; 49(5–6):203–7.
Genuis SJ, Bouchard TP. Combination of Micronutrients for Bone (COMB) Study: bone density after micronutrient intervention. J Environ Public Health. 2012; 2012:354151.
Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2010.
Body JJ. How to manage postmenopausal osteoporosis? Acta Clin Belg. 2011; 66:443–7.
http://www.vitamindcouncil.org/about-vitamin-d/how-do-i-get-the-vitamin-d-my-body-needs/. Accessed September 12, 2013 .
Bailey RL, Dodd KW, Goldman JA, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010; 140:817–22.
Ervin RB, Wang CY, Wright JD, Kennedy-Stephenson J. Dietary intake of selected minerals for the United States population: 1999–2000. Adv Data. 2004; 1–5.
Brown LM. Helicobacter pylori: epidemiology and routes of transmission. Epidemiol Rev. 2000; 22(2):283–97.
Fox J, Sheh A. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes. 2013; 4(6):43–68.
Hannan MT, Felson DT, Dawson-Hughes B, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 2000; 15:710–20.
Shea MK, Booth SL, Massaro JM, et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol. 2008; 167(3):313–20.
Binkley N, Harke J, Krueger D, et al. Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res. 2009; 24:983–91.
Pizzorno L. Vitamin K2: optimal levels essential for the prevention of age-associated chronic disease. August 2011. Longevity Medicine Review. (http://www.lmreview.com/articles/view/Vitamin-K2-Essential-for-Prevention-of-Age-Associated-Chronic-Disease/). Accessed September 14, 2013 .
Booth SL, Broe KE, Gagnon DR, et al. Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr. 2003; 77:512–16.
Booth SL, Tucker KL, Chen H, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr. 2000; 71:1201–8.
Cheung AM, Tile L, Lee Y, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008; 5:e196.
Braam LA, Knapen MH, Geusens P, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int. 2003; 73:21–6.
Op. cit., Pizzorno L. Vitamin K2: optimal levels essential for the prevention of age-associated chronic disease. August 2011. Longevity Medicine Review. (http://www.lmreview.com/articles/view/Vitamin-K2-Essential-for-Prevention-of-Age-Associated-Chronic-Disease/). Accessed September 14, 2013 .
Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999; 69:74–9.
van Summeren MJ, van Coeverden SC, Schurgers LJ, et al. Vitamin K status is associated with childhood bone mineral content. Br J Nutr. 2008; 100:852–8.
Inoue T, Fujita T, Kishimoto H, et al. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab. 2009; 27:66–75.
Iwamoto J, Sato Y. Menatetrenone for the treatment of osteoporosis. Expert Opin Pharmacother. 2013; 14:449–58.
Bunyaratavej N, Kittimanon N, Jitivirai T, Tongthongthip B. Highly recommended dose of MK4 for osteoporosis. J Med Assoc Thai. 2009; 92(Suppl 5):S4–6.
Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008; 100(4):530–47.
Koitaya N, Ezaki J, Nishimuta M, et al. Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women. J Nutr Sci Vitaminol (Tokyo). 2009; 55:15–21.
Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002; 1570(1):27–32.
Schurgers LJ, Teunissen KJ, Hamulyák K, et al. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007; 109(8):3279–83.
Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013; 24(9):2499–507.
Westenfeld R, Krueger T, Schlieper G, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012; 59(2):186–95.
Knapen MH, Schurgers LJ, Vermeer C. Vitamin K(2) supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007; 18(7):963–72.
Ishida Y. [Vitamin K2]. Clin Calcium. 2008; 18(10):1476–82.
Cockayne S, Adamson J, Lanham-New S, et al. Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2006; 166(12):1256–61.
Adams J, Pepping J. Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm. 2005; 62(15):1574–81.
Bügel S. Vitamin K and bone health in adult humans. Vitam Horm. 2008; 78:393–416.
Kanellakis S, Moschonis G, Tenta R, et al. Changes in parameters of bone metabolism in postmenopausal women following a 12-month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K (2)): the Postmenopausal Health Study II. Calcif Tissue Int. 2012; 90(4):251–62.
Op. cit., Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013; 24(9):2499–507.
Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. Brit Med J. 2011; 342:d2040.
Wallace RB, Wactawski-Wende J, O’Sullivan MJ, et al. Urinary tract stone occurrence in the Women’s Health Initiative randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011; 94(1):270–7.
Pizzorno L. Vitamin D and vitamin K team up to lower CVD risk. Longevity Medicine Review, 2009 (http://www.lmreview.com/articles/view/vitamin-d-and-vitamin-k-team-up-to-lower-cvd-risk-part-II/) .
Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000; 20(2):317–27.
Spronk HM, Soute BA, Schurgers LJ, et al. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res. 2003; 40(6):531–7.
Theuwissen E, Teunissen K, Spronk H, et al. Effect of low-dose supplements of menaquinone-7 [vitamin K2(35)] on the stability of oral anticoagulant treatment: dose-response relationship in healthy volunteers. J Thromb Haemost. 2013; 11(6):1085–92.
Tahir F, Riaz H, Riaz T, et al. The new oral anti-coagulants and the phase 3 clinical trials – a systematic review of the literature. Thromb J. 2013; 11(1):18.
Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet. 2013; 52(2):69–82.
Pfeilschifter W, Luger S, Brunkhorst R, et al. The gap between trial data and clinical practice – an analysis of case reports on bleeding complications occurring under dabigatran and rivaroxaban anticoagulation. Cerebrovasc Dis. 2013; 36(2):115–9.
Rude RK, Singer FR, Gruber HE. Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr. 2009; 28:131–41.
Kanazawa I, Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. A case of magnesium deficiency associated with insufficient parathyroid hormone action and severe osteoporosis. Endocr J. 2007; 54:935–40.
Sahota O, Mundey MK, San P, Godber IM, Hosking DJ. Vitamin D insufficiency and the blunted PTH response in established osteoporosis the role of magnesium deficiency. Osteoporos Int. 2006; 17:1013–21.
Reginster JY, Strause L, Deroisy R, Lecart MP, Saltman P, Franchimont P. Preliminary report of decreased serum magnesium in postmenopausal osteoporosis. Magnesium. 1989; 8:106–9.
Rude RK, Olerich M. Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy. Osteoporos Int. 1996; 6:453–61.
Rude RK, Adams JS, Ryzen E, et al. Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab. 1985; 61(5):933–40.
Chou HF, Schwartz R, Krook L, Wasserman RH. Intestinal calcium absorption and bone morphology in magnesium deficient chicks. Cornell Vet. 1979; 69:88–103.
Sader MS, Legeros RZ, Soares GA. Human osteoblasts adhesion and proliferation on magnesium-substituted tricalcium phosphate dense tablets. J Mater Sci Mater Med. 2009; 20:521–7.
National Academy of Sciences. A Report of the Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001.
Tranquilli AL, Lucino E, Garzetti GG, Romanini C. Calcium, phosphorus and magnesium intakes correlate with bone mineral content in postmenopausal women. Gynecol Endocrinol. 1994; 8:55–8.
Tucker KL, Hannan MT, Chen H, Cupples LA, Wilson PW, Kiel DP. Potassium, magnesium, and fruit and vegetable intakes are associated with greater bonemineral density in elderly men and women. Am J Clin Nutr. 1999; 69:727–36.
Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two year controlled trial of peroral magnesium in osteoporosis. Magnes Res. 1993; 6:155–63.
Freeland-Graves JH, Turnlund JR. Deliberations and evaluations of the approaches, endpoints and paradigms for manganese and molybdenum dietary recommendations. J Nutr. 1996; 126:2435S–40S.
Strause L, Saltman P, Glowacki J. The effect of deficiencies of manganese and copper on osteoinduction and on resorption of bone particles in rats. Calcif Tissue Int. 1987; 41:145–50.
Strause LG, Hegenauer J, Saltman P, Cone R, Resnick D. Effects of long-term dietary manganese and copper deficiency on rat skeleton. J Nutr. 1986; 116:135–41.
Strause L, Saltman P, Smith KT, Bracker M, Andon MB. Spinal bone loss in postmenopausal women supplemented with calcium and trace minerals. J Nutr. 1994; 124:1060–4.
Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis – a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab. 2002; 87:2060–6.
Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int. 2001; 69:121–9.
Li C, Paris O, Siegel S, et al. Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment. J Bone Miner Res. 2010; 25:968–75.
Boivin G, Doublier A, Farlay D. Strontium ranelate – a promising therapeutic principle in osteoporosis. J Trace Elem Med Biol. 2012; 26:153–6.
Saidak Z, Marie PJ. Strontium signaling: molecular mechanisms and therapeutic implications in osteoporosis. Pharmacol Ther. 2012; 136:216–26.
Roux C, Fechtenbaum J, Kolta S, Isaia G, Andia JB, Devogelaer JP. Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis. 2008; 67:1736–8.
Seeman E, Devogelaer JP, Lorenc R, et al. Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia. J Bone Miner Res. 2008; 23:433–8.
Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005; 90:2816–22.
Audran M, Jakob FJ, Palacios S, et al. A large prospective European cohort study of patients treated with strontium ranelate and followed up over 3 years. Rheumatol Int. 2013; 33:2231–9.
Kaufman JM, Audran M, Bianchi G, et al. Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men. J Clin Endocrinol Metab. 2013; 98:592–601.
Osborne V, Layton D, Perrio M, et al. Incidence of venous thromboembolism in users of strontium ranelate: an analysis of data from a prescription-event monitoring study in England. Drug Saf. 2010; 33(7):579–91.
Le Merlouette M, Adamski H, Dinulescu M, et al. [Strontium ranelate-induced DRESS syndrome]. Ann Dermatol Venereol. 2011; 138(2):124–8.
Jonville-Bera AP, Autret-Leca E. [Adverse drug reactions of strontium ranelate(Protelos® in France]. Presse Med. 2011; 40(10):e453–62.
Anonymous. Strontium: new drug. Postmenopausal osteoporosis: too many unknowns. Prescrire Int. 2005; 14(80):207–11.
Anonymous. Strontium ranelate: too many adverse effects (continued) Do not use. Prescrire Int. 2012; 21(125):72.
Protelos, INN-Strontium ranelate – European Medicines (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000560/WC500045522.pdf). Accessed September 14, 2013 .
Neufeld EB, Boskey AL. Strontium alters the complexed acidic phospholipid content of mineralizing tissues. Bone. 1994; 15(4):425–30.
Ozgur S, Sumer H, Kocoglu G. Rickets and soil strontium. Arch Dis Child. 1996; 75(6):524–6.
Centers for Disease Control’s Agency for Toxic Substances and Disease Registry Health Effects of Strontium report (http://www.atsdr.cdc.gov/ToxProfiles/tp159-c3.pdf) .
Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest. 1990; 85:632–9.
Yang S, Madyastha P, Bingel S, Ries W, Key L. A new superoxide-generating oxidase in murine osteoclasts. J Biol Chem. 2001; 276:5452–8.
Sontakke AN, Tare RS. A duality in the roles of reactive oxygen species with respect to bone metabolism. Clin Chim Acta. 2002; 318:145–8.
Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med. 2001; 31:509–19.
Fatokun AA, Stone TW, Smith RA. Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species. Eur J Pharmacol. 2008; 587:35–41.
Welch A, Macgregor A, Jennings A, Fairweather-Tait S, Spector T, Cassidy A. Habitual flavonoid intakes are positively associated with bone mineral density in women. J Bone Miner Res. 2012; 27:1872–78.
Hardcastle AC, Aucott L, Reid DM, Macdonald HM. Associations between dietary flavonoid intakes and bone health in a Scottish population. J Bone Miner Res. 2011; 26:941–7.
Hooshmand S, Arjmandi BH. Viewpoint: dried plum, an emerging functional food that may effectively improve bone health. Ageing Res Rev. 2009; 8:122–7.
Muraki S, Yamamoto S, Ishibashi H, et al. Diet and lifestyle associated with increased bone mineral density: cross-sectional study of Japanese elderly women at an osteoporosis outpatient clinic. J Orthop Sci. 2007; 12:317–20.
Hegarty VM, May HM, Khaw KT. Tea drinking and bone mineral density in older women. Am J Clin Nutr. 2000; 71:1003–7.
Devine A, Hodgson JM, Dick IM, Prince RL. Tea drinking is associated with benefits on bone density in older women. Am J Clin Nutr. 2007; 86:1243–7.
Chen Z, Pettinger MB, Ritenbaugh C, et al. Habitual tea consumption and risk of osteoporosis: a prospective study in the women’s health initiative observational cohort. Am J Epidemiol. 2003; 158:772–81.
Hamdi KI, Aydin S, Gemalmaz A, et al. Habitual tea drinking and bone mineral density in postmenopausal Turkish women: investigation of prevalence of postmenopausal osteoporosis in Turkey (IPPOT Study). Int J Vitam Nutr Res. 2007; 77:389–97.
Kyriazopoulos P, Trovas G, Charopoulos J, Antonogiannakis E, Galanos A, Lyritis G. Lifestyle factors and forearm bone density in young Greek men. Clin Endocrinol (Oxf). 2006; 65:234–8.
Saitoglu M, Ardicoglu O, Ozgocmen S, Kamanli A, Kaya A. Osteoporosis risk factors and association with somatotypes in males. Arch Med Res. 2007; 38:746–51.
Holzer N, Braun KF, Ehnert S, et al. Green tea protects human osteoblasts from cigarette smoke-induced injury: possible clinical implication.Langenbecks Arch Surg. 2012; 397:467–74.
Shen CL, Cao JJ, Dagda RY, et al. Green tea polyphenols benefits body composition and improves bone quality in long-term high-fat diet-induced obese rats. Nutr Res. 2012; 32:448–57.
Shen CL, Yeh JK, Cao JJ, Chyu MC, Wang JS. Green tea and bone health: evidence from laboratory studies. Pharmacol Res. 2011; 64:155–61.
Atmaca A, Kleerekoper M, Bayraktar M, Kucuk O. Soy isoflavones in the management of postmenopausal osteoporosis. Menopause. 2008; 15:748–57.
Zhang X, Shu XO, Li H, et al. Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch Intern Med. 2005; 165:1890–5.
Brink E, Coxam V, Robins S, Wahala K, Cassidy A, Branca F. Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study.Am J Clin Nutr. 2008; 87:761–70.
Alekel DL, Van Loan MD, Koehler KJ, et al. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr. 2010; 91:218–30.
Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med. 2011; 171:1363–9.
Kenny AM, Mangano KM, Abourizk RH, et al. Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr. 2009; 90:234–42.
Vupadhyayula PM, Gallagher JC, Templin T, Logsdon SM, Smith LM. Effects of soy protein isolate on bone mineral density and physical performance indices in postmenopausal women – A 2-year randomized, double-blind, placebo-controlled trial. Menopause. 2009; 16:320–8.
Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002; 17:1904–12.
Marini H, Minutoli L, Polito F, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007; 146:839–47.
Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women: meta-analysis of randomized controlled trials. Clin Nutr. 2008; 27:57–64.
Liu J, Ho SC, Su YX, Chen WQ, Zhang CX, Chen YM. Effect of long-term intervention of soy isoflavones on bone mineral density in women: a meta-analysis of randomized controlled trials. Bone. 2009; 44:948–53.
Marini H, Bitto A, Altavilla D, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab. 2008; 93:4787–96.
Taylor CK, Levy RM, Elliott JC, Burnett BP. The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies. Nutr Rev. 2009; 67:398–415.
Hooper L, Madhavan G, Tice JA, Leinster SJ, Cassidy A. Effects of isoflavones on breast density in pre- and post-menopausal women: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update. 2010; 16:745–60.
Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies.Breast Cancer Res Treat. 2011; 125:315–23.
Andres S, Abraham K, Appel KE, Lampen A. Risks and benefits of dietary isoflavones for cancer. Crit Rev Toxicol. 2011; 41:463–506.
Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;CD001395.
Prior JC. Perimenopause: the complex endocrinology of the menopausal transition. Endocr Rev. 1998; 19:397–28.
Scheven BA, Damen CA, Hamilton NJ, Verhaar HJ, Duursma SA. Stimulatory effects of estrogen and progesterone on proliferation and differentiation of normal human osteoblast-like cells in vitro. Biochem Biophys Res Commun. 1992; 186:54–60.
Schmidmayr M, Magdolen U, Tubel J, Kiechle M, Gurgkart R, Seifert-Klauss V. Progesterone enhances differentiation of primary human osteoblasts in long-term cultures. The influence of concentration and cyclicity of progesterone on proliferation and differentiation of human osteoblasts in vitro. Geburtshilfe Frauenheilk. 2008; 68:722–8.
Franck F, Ehle A, Wimmer T, Kiechler M, Seifert-Klauss V. Zum Einfluss von Ernahrung und Aktivitat auf die Knochendichte perimenopausaler Frauen – die Perimenopausale Knochendichte und Ovulation (PEKNO)-Studie. Geburtshilfe Frauenheilk. 2011; 71:409.
Ehle A, Muller D, Boppel K, Kiechle M, Siefert-Klauss V. Cycle-evaluation and cycle patterns in peri-menopausal women: the PEKNO study.Geburtshilfe Frauenheilk. 2008; 2008:S182.
Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev. 1990; 11:386–98.
Anonymous. Effects of hormone therapy on bone mineral density: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. The Writing Group for the PEPI. J Am Med Assoc. 1996; 276:1389–96.
Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. J Am Med Assoc. 2002; 287:2668–76.
Leowattana W. DHEA(S): the fountain of youth. J Med Assoc Thai. 2001; 84(Suppl 2):S605–12.
Ghebre MA, Hart DJ, Hakim AJ, et al. Association between DHEAS and bone loss in postmenopausal women: a 15-year longitudinal population-based study. Calcif Tissue Int. 2011; 89:295–302.
Papierska L, Rabijewski M, Kasperlik-Zaluska A, Zgliczynski W. Effect of DHEA supplementation on serum IGF-1, osteocalcin, and bone mineral density in postmenopausal, glucocorticoid-treated women. Adv Med Sci. 2012; 57:51–7.
Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: The Chingford Study. J Rheumatol. 1993; 20:331–5.
Zhai G, Hart DJ, Valdes AM, et al. Natural history and risk factors for bone loss in postmenopausal Caucasian women: a 15-year follow-up population-based study. Osteoporos Int. 2008; 19:1211–7.
Tok EC, Ertunc D, Oz U, Camdeviren H, Ozdemir G, Dilek S. The effect of circulating androgens on bone mineral density in postmenopausal women. Maturitas. 2004; 48:235–42.
Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men.Clin Endocrinol (Oxf). 2000; 53:561–8.
Martel C, Sourla A, Pelletier G, et al. Predominant androgenic component in the stimulatory effect of dehydroepiandrosterone on bone mineral density in the rat. J Endocrinol. 1998; 157:433–42.
Tucker KL, Morita K, Qiao N, Hannan MT, Cupples LA, Kiel DP. Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study. Am J Clin Nutr. 2006; 84:936–42.
Heaney RP. Effects of caffeine on bone and the calcium economy. Food Chem Toxicol. 2002; 40:1263–70.
Howe TE, Shea B, Dawson LJ, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2011;CD000333.
Engelke K, Kemmler W, Lauber D, Beeskow C, Pintag R, Kalender WA. Exercise maintains bone density at spine and hip EFOPS: a 3-year longitudinal study in early postmenopausal women. Osteoporos Int. 2006; 17:133–42.
Kranz S, Lin PJ, Wagstaff DA. Children’s dairy intake in the United States: too little, too fat? J Pediatr. 2007; 151:642–6.
Moore LL, Singer MR, Qureshi MM, Bradlee ML, Daniels SR. Food group intake and micronutrient adequacy in adolescent girls. Nutrients. 2012; 4:1692–708.
Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357:266–81.
Whiting SJ, Healey A, Psiuk S, Mirwald R, Kowalski K, Bailey D. Relationship between carbonated and other low nutrient dense beverages and bone mineral content of adolescents. Nutr Res. 2001; 21:1107–15.
McGartland C, Robson PJ, Murray L, et al. Carbonated soft drink consumption and bone mineral density in adolescence: The Northern Ireland Young Hearts project. J Bone Miner Res. 2003; 18:1563–9.
Seeman E, Compston J, Adachi J, et al. Non-compliance: the Achilles’ heel of anti-fracture efficacy. Osteoporos Int. 2007; 18:711–9.
Siris ES, Selby PL, Saag KG, Borgstrom F, Herings RM, Silverman SL. Impact of osteoporosis treatment adherence on fracture rates in North America and Europe. Am J Med. 2009; 122:S3–13.
Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011; 26:1729–39.
Cvijetic S, Colic BI, Keser I, Cecic I, Satalic Z, Blanusa M. Peak bone density in Croatian women: variations at different skeletal sites. J Clin Densitom. 2008; 11:260–5.
Lorentzon M, Mellstrom D, Ohlsson C. Age of attainment of peak bone mass is site specific in Swedish men – The GOOD study. J Bone Miner Res. 2005; 20:1223–7.
Matkovic V, Jelic T, Wardlaw GM, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest. 1

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