Osteoporosis International

, Volume 15, Issue 5, pp 389–395

Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels.

  • P. Pennisi
  • S. S. Signorelli
  • S. Riccobene
  • G. Celotta
  • L. Di Pino
  • T. La Malfa
  • C. E. Fiore
Original Article


Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score −1.71±1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score −2.5±0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3±3.1 vs 27.7±3.3 ng/ml, P<0.01, and 8.4±2.3 vs 12.5±1.4 μg/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9±138.9 vs 272.2±79.4 µg/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5±1.07 vs 3.4±1.05 pmol/l, and 0.37±0.07 vs 0.36±0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG–RANKL system.


Atherosclerosis Bone mineral density CrossLaps Osteocalcin Osteoprotegerin 


  1. 1.
    Frye MA, Melton LJ III, Bryant SC, Fitzpatrick LA, Wahner HW, Schwartz RS, Riggs BL (1992) Osteoporosis and calcification of the aorta. Bone Miner 19:185–194PubMedGoogle Scholar
  2. 2.
    Vogt MT, San Valentin R, Forrest KY, Nevitt MC, Cauley JA (1997) Bone mineral density and aortic calcification: the study of osteoporotic fractures. J Am Geriatr Soc 45:140–145Google Scholar
  3. 3.
    Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O’Donnel CJ, Wilson PWF (2001) Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int 68:271–276PubMedGoogle Scholar
  4. 4.
    Dent CE, Engelbrecht HE, Godfrey RC (1968) Osteoporosis of lumbar vertebrae and calcification of abdominal aorta in women living in Durban. BMJ 4:76–79PubMedGoogle Scholar
  5. 5.
    Reck P, Hansen MA, Hassager C (1999) The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 106:273–278CrossRefPubMedGoogle Scholar
  6. 6.
    van der Klift M, Pols HAP, Hak AE, Witteman JCM, Hofman A, de Laet CEDH (2002) Bone mineral density and the risk of peripheral arterial disease: the Rotterdam Study. Calcif Tissue Int 70:443–449CrossRefPubMedGoogle Scholar
  7. 7.
    Tanko LB, Bagger YZ, Christiansen C (2003) Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 73:15–20CrossRefPubMedGoogle Scholar
  8. 8.
    Aoyagi K, Ross PD, Orloff J, Davis JW, Katagiri H, Wasnich RD (2001) Low bone density is not associated with aortic calcification. Calcif Tissue Int 69:20–24CrossRefPubMedGoogle Scholar
  9. 9.
    Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811Google Scholar
  10. 10.
    Price PA, Faus SA, Williamson MK (2000) Warfarin-induced artery calcification is accelerated by growth and by vitamin D. Thromb Vasc Biol 20:317–327Google Scholar
  11. 11.
    Moon J, Bandy B, Davison AJ (1992) Hypothesis: etiology of atherosclerosis and osteoporosis. Are imbalances in the calciferol endocrine system implicated? J Am Coll Nutr 1:567–583Google Scholar
  12. 12.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Lin Tan H, Xu W, Lacey DL, Boyle WJ (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268PubMedGoogle Scholar
  13. 13.
    Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, Nishizawa Y (2002) Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 106:1192–1194CrossRefPubMedGoogle Scholar
  14. 14.
    Nakayama H, Yano Y, Sagara Y, Ando K, Kasai Y, Taketani Y (1997) Clinical usefulness of urinary CrossLaps as a sensitive marker of bone metabolism. Endocrine J 44:479–484Google Scholar
  15. 15.
    Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15:2–12PubMedGoogle Scholar
  16. 16.
    Schoppet M, Preissner KT, Hofbauer LC (2002) RANKL ligand and osteoprotegerin. Paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 22:549–553CrossRefPubMedGoogle Scholar
  17. 17.
    Paffenbarger RS Jr, Wing AL, Hyde RT (1978) Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol 108:161–175PubMedGoogle Scholar
  18. 18.
    Ireland P, Jolley D, Giles G, O’Dea K, Powkes J, Ritishauer I, Wahlqvist ML, Williams J (1994) A food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pac J Clin Nutr 3:19–31Google Scholar
  19. 19.
    Spence JD (2002) Ultrasound measurement of carotid plaque as a surrogate outcome for coronary artery disease. Am J Cardiol 89:10B–15BCrossRefPubMedGoogle Scholar
  20. 20.
    Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R (1986) Intima plus media thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 74:1399–1406PubMedGoogle Scholar
  21. 21.
    Signorelli SS, Sciacchiano S, Costa MP, Di Pino L, Pennisi G, Caschetto S (2000) Behaviour of the carotid wall in menopausal women with and without arterial hypertension. Maturitas 35:39–43CrossRefPubMedGoogle Scholar
  22. 22.
    Graafmans WC, Van Lingen A, Ooms ME, Bezemer PD, Lips P (1996) Ultrasound measurements in the calcaneus. Precision and its relation with bone mineral density of the heel, hip and lumbar spine. Bone 19:97–100CrossRefPubMedGoogle Scholar
  23. 23.
    Glüer CC (1997) Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. The International Quantitative Ultrasound Consensus Group. J Bone Miner Res 12:1280–1288PubMedGoogle Scholar
  24. 24.
    Cheng S, Lian M, Wang L (1998) Evaluation of the precision of a new scanning-dry ultrasound device QUS-2. Osteoporos Int 8 [Suppl 3]:62Google Scholar
  25. 25.
    Fiore CE, Barone R, Pennisi P, Pavone V, Riccobene S (2002) Bone ultrasonometry, bone density, and turnover markers in type 1 Gaucher disease. J Bone Miner Metab 20:34–38CrossRefPubMedGoogle Scholar
  26. 26.
    Burger H, van Daele PL, Odding E, Valkenburg HA, Hofman A, Grobbee DE, Schutte HE, Birkenhager JC, Pols HA (1996) Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The Rotterdam Study. Arthritis Rheum 39:81–86PubMedGoogle Scholar
  27. 27.
    Uyama O, Yoshimoto Y, Yamamoto Y, Kawai A (1997) Bone changes and carotid atherosclerosis in postmenopausal women. Stroke 28:1730–1732PubMedGoogle Scholar
  28. 28.
    Laroche M, Poullies JM, Ribot C, Bendayan P, Bernard J, Boccalon H, Mazieres B (1994) Comparison of the bone mineral content of the lower limbs in men with ischaemic atherosclerotic disease. Clin Rheumatol 13:611–614PubMedGoogle Scholar
  29. 29.
    Slemenda C, Hui SL, Longcope C, Johnston CC (1987) Sex steroids and bone mass: a study of changes about the time of menopause. J Clin Invest 80:1261–1269PubMedGoogle Scholar
  30. 30.
    Gaspard UJ, Gottal JM, van den Brule FA (1995) Postmenopausal changes of lipid and glucose metabolism: a review of their main aspects. Maturitas 21:171–178CrossRefPubMedGoogle Scholar
  31. 31.
    Parhami F, Morrow AD, Balucan J, Letinger N, Watson AD, Tintut Y, Berliner JA, Demer LL (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680–687Google Scholar
  32. 32.
    Tintut Y, Demer LL. Recent advances in multifactorial regulation of vascular calcification. Curr Opin Lipidol 12:555, 560CrossRefPubMedGoogle Scholar
  33. 33.
    McKane WR, Khosla S, Risteli J, Robins SP, Muhs JM, Riggs BL (1997) Role of estrogen deficiency in pathogenesis of secondary hyperparathyroidism and increased bone resorption in elderly women. Proc Assoc Am Physicians 109:174–180PubMedGoogle Scholar
  34. 34.
    Reginster JY, Derisy R, Pirenne H, Frederick I, Dewe W, Albert A, Collette J, Zheng SX, Gosset C (1999) High prevalence of low femoral bone mineral density in elderly women living in nursing homes or community dwelling: a plausible role of increased parathyroid hormone secretion. Osteoporos Int 9:121–128CrossRefPubMedGoogle Scholar
  35. 35.
    Rostand SG, Drueke TB (1999) Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 56:383–392CrossRefPubMedGoogle Scholar
  36. 36.
    Riggs BL, Khosla S, Melton LJ (1998) A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763–773PubMedGoogle Scholar
  37. 37.
    Jie KG, Bots ML, Vermeer C, Witteman JC, Grobbee DE (1996) Vitamin K status and bone mass in women with and without aortic atherosclerosis: a population-based study. Calcif Tissue Int 59:352–356CrossRefPubMedGoogle Scholar
  38. 38.
    Minne HW, Pfeilschifter J, Scharla S, Mutschelknauss A, Schwarz B, Krempien R, Ziegler R (1984) Inflammation-mediated osteopenia in the rat: a new animal model for pathological loss of bone mass. Endocrinology 115:50–54PubMedGoogle Scholar
  39. 39.
    Fiore CE, Clementi G, Prato A, Foti R, Conforto G (1988) Bone mineral content of the hyperprolactinemic rat femur by single photon absorptiometry. Horm Metab Res 20:40–43PubMedGoogle Scholar
  40. 40.
    Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop 232:210–216PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2003

Authors and Affiliations

  • P. Pennisi
    • 1
  • S. S. Signorelli
    • 2
  • S. Riccobene
    • 1
  • G. Celotta
    • 2
  • L. Di Pino
    • 2
  • T. La Malfa
    • 1
  • C. E. Fiore
    • 1
  1. 1.Department of Internal MedicineUniversity of Catania OVECataniaItaly
  2. 2.Department of Internal Medicine and Medical Specialities, Section of Medical AngiologyUniversity of CataniaCataniaItaly

Personalised recommendations