Abstract:Osteoporosis,is one of the global problem which causes deterioration of the bone microarchitecture and thereby  results in fragility fractures, pain and disability. It is usually associated with old age, hormonal insufficiency.Recently it is known to be associated with type 2 diabetes. Type 2 Diabetes mellitus is a pandemic metabolic disorder and is a known to be a major risk factor of osteoporotic fractures. Bone is continuously renewed and remodeled and regulated by various factors such as the balance between osteoblast and osteoclast, leptin mediated pathway, leptin regulation of bone resorption and through cannabinoid receptors. But in type 2 DM because of insulin insensitivity, leptin insensitivity, altered osteoblast and osteoclast function, there occurs alteration of bone remodeling which results in osteoporosis. DM mediated osteoporosis is multifactorial. This review explains the pathophysiology of type 2 diabetes mediated osteoporosis


DM is a group of pandemic debilitating metabolic diseasesfeaturing chronic hyperglycemia which resultsfrom defective insulin secretion and/or insulin action. (1) It has been found to be associated with metabolic bone diseases, osteoporosis and low-impact fractures, as well as other bone-related events including falls in geriatric patients(2,3). This displays the inferior quality and strength of bone in diabetes mellitus which further aggravates the risk of osteoporosis(4). Based on 2001 census, approximately 163 million Indians who are above the age of 50 are affected from osteoporosis and it is expected to increase to 230 million by 2015(5)



Osteoblasts and osteoclasts:

Bone is a structural framework of the body, which undergoes continuous microstructural remodeling throughout life to accommodate mechanical stress and calcium demand(6). Osteoblasts and osteoclasts are the two important cells which play critical role in bone metabolism. Osteoblasts produces bone matrix while osteoclast resorb bone matrix. In normal condition, the resorption will be followed by new bone formation, to keep the balance of bone mass to suit the change of bone mechanical environment and to repair micro damage(7)

Osteoclast-mediated bone resorption is initiated by osteoblasts. Osteoblasts initiates the proliferation of the precursors of osteoclasts and their differentiation in to mature osteoclasts by secreting a cytokine called macrophage colony stimulating factor(MCSF)[8,9].Osteoblasts also secrete the key mediator for osteoclastogenesis, receptor activator of nuclear factor-κB ligand (RANKL). RANKL binds to its receptor (RANK) on the plasma membrane of osteoclast precursors. Moreover, to counterbalance RANKL action, osteoblastsalsosynthesize and secrete osteoprotegerin (OPG), which is a soluble decoy receptor capable of inhibiting RANK-RANKL interaction and osteoclastogenesis[10].



Leptin is a fat derived hormone secreted by adipocytes which has an important role in the signaling and regulation of food intake and energy expenditure (11).Leptin receptors are not only present in CNS but also in peripheral tissues namely skeletal muscle, liver and bone. Leptin receptors are also found in osteoblasts, osteoclasts and bone marrow stromal cells which suggests that leptin can regulate bone metabolism also. (12). Leptin directly acts on Bone marrow derived stromal cells (BMSCs), osteoblasts and osteoclasts and inhibits bone resorption and stimulates bone formation. But when the concentration of leptin is higher it induces apoptosis in BMSCs which results in decrease in bone formation and increase in bone resorption. (13,14)Leptin deficient ob/ob mice has shown cancellous bone mass increase and decrease in bone length and mass (15).But leptin replacement to this mice corrected the skeletal abnormalities(16). This leptin pathway has shown to regulate the sympathetic tone of the bone and modulate adrenergic signaling locally through osteoblastic β2 adrenergic receptor.(17)



Insulin was found to induce osteogenic action directly by increasing cell proliferation, differentiation and expression of type 1 collagen and osteocalcin in human osteoblast like
MG-63 cells. So insulin directly helps in the bone formation.(18). Thus insulin serve as anabolic signals to promote bone formation (19,20)



Cocaine and Amphetamine regulated transcript is  a neuropeptide precursor protein which is involved in the regulation of food intake and energy expenditure(21).It  has also a role in the regulation of bone resorption(22).CART knockout mice were found to be osteoporotic because of an increase in bone resorption (21). Reduced CART expression induces an increase in bone resorption and increased CART expression produces a higher bone mass. Decreased CART expression in ob/ob mice can be restored by treatment of leptin (22)




Endocannabinoids are endogenous agonists which mediates it action through CB1 and CB2 receptors (23). CB1 receptors activation in bone inhibits the release of norepinephrine by sympathetic neurons and decreases the tonic sympathetic restrain of bone formation (24,25). Inactivating CB1 receptor produces increased Bone Mineral Density (26) whereas CB2 null mice have increased cancellous bone loss (27) and Invitro studies have shown that CB2 signalling maintains bone mass by two mechanisms (i) stimulating the osteoblasts directly and (ii) inhibiting RANKL expression both directly and indirectly. These evidences prove that the endocannabinoid system plays a major role in maintenance of bone mass.



  1. 1.    Increased osteoclast function– Hyperglycemia induces production of macrophage colony stimulating factor, Tumor Necrosis Factor –α and Rank L, all of which are osteoblast derived activator of osteoclast proliferation and differentiation. Further suppression of osteoblast proliferation takes place by decreasing osteocalcin and osteopontin expressions. Bone quality is also reduced as a result of advanced glycation end products, which eventually results in fractures. (6)


2. Insulin and CB1 – Insulin downregulatesEndocannabinoid levels or upregulatesendocannabinoid degradation (28). But in hyperglycemia due to insufficient or useless insulin there is permanent increase in both anandamide and 2- arachidonyl glycerol levels. This causes overstimulation of CB1 and TRPV1 vs CB2. Insulin sensitivity is further decreased by 2-arachidonyl glycerol levels and promotes the positive vicious cycle.

Over stimulation of CB1 promotes osteoclast production and decreases the proliferation of osteoblast thus enhances bone resorption.


3. Leptin- elevated plasma leptin levels or hyperleptinemia, have been demonstrated to correlate with hyperphagia, insulin resistance and other markers of the metabolic syndrome including obesity, hyperlipidemia and hypertension, independent of total adiposity.Insulin resistance have been shown to rapidly enhance plasma leptin levels and subsequently develop tissueleptin resistance. In a malfunctioning leptin signaling system there is permanently elevated endocannabinoidslevels.(29). Leptin resistance further enhances bone resorption throughleptin mediated pathway and CART mediated pathway(17,22) and it also induces apoptosis in BMSCs



Diabetes mediated osteoporosis is very common and the pathway leading to it has a multifactorial origin. These pathway give us an insight that not only osteoblast and osteoclast has a role in diabetes mediated bone loss but also there exists other neural and hormonal signaling pathways like leptin resistance, insulin resistance and endocannabinoid system dysfunction. Thus this review help us to understand the pathophysiology of osteoporosis in type II diabetes mellitus and thereby give an insight regarding the prevention and treatment of it at an early stage. To detect an early bone loss in type II DM bone densitometry should be monitored at regular intervals and if any deterioration is found early treatment with vitamin D supplementation and calcium can be given to promote bone formation. Exercises can be included for the subjects as soon as they are diagnosed with type II diabetes.. Generally, two types of exercises are recommended for osteoporosis. They are Weight-bearing exercises and  Strength training or resistance exercises
Weight-bearing exercises are those in which the muscles and bones bear the weight of the person and work against gravity they are walking, jogging, stair climbing etc… Persons having osteoporosis should start with a gentle exercise such as walking on level ground that has been shown to increases BMD(30) . Strength training or Resistance exercises are activities in which the body is moved through its range of motion against some kind of resistance.Theseexrecises has a direct effect on bone formation and remodeling.Examples of these exerxisesareLifting weights, push-ups, and squats apply resistance against the bones by contracting the muscles and pulling upon the tendons..( 31,32)Strengthening the muscles which helps in daily tasks and postural exercises can prevent falls and strengthens the spine. (33,34)





























In hyperglycemia, there is  insulin resistance and leptin resistance. Insulin resistance cause over stimulation of CB1 receptors which inturn stimulate osteoclastic activity. It also causes reduction in the sympathetic tone through CB2 receptors which further enhances the osteoclastic activity. Leptin resistance causes reduced sympathetic tone. Hyperglycemia itself is a trigger for Monocyte CSF and Rank –L activation which again promotes osteoclastic activity.


In normal bonremodelling there exists a balance between osteoblasts and osteoclasts. CB1 induces osteoclastic activity but CB2 receptors promotesosteoblastic activity. Leptin and CART also helps in bone formation



















































  1. American diabetes association. Diagnosis and classification of diabetes mellitus. Diabetes care 2009;32 suppl:S62-S67.
  2. Chau DL, Edelman SV. Osteoporosis and diabetes. Clin Diabetes 2002; 20: 153-157
  3. Brown SA, Sharpless JL. Osteoporosis: an under-appreciated complication of diabetes. Clin Diabetes 2004;22:10-20
  4. GrupaRoboczaZaleceniaPostepowaniadiagnostycznego I lecznicnego w osteoporozic. Obnoizenieczestoscizlamanpoprezefektywnaprofilaktyke I leczenie. Terapia2007;9:1-39
  5. NordinBEC.International patterns of osteoporosis, Clin. Orthop1966;45:17-30
  6. Wongdee K, Charoenphandhu N. Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms. World J Diabetes 2011;2(3): 41-48.
  7. Zhidao Xia (Botnar Research centre, Nuffield Department of Orthopaedic Surgery, University of Oxford) Tissue engineering of bone: The role of osteoblasts and osteoclasts.
  8. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289: 1504-1508
  9. Matsuo K, Irie N. Osteoclast- osteoblast communication. Arch BiochemBiophys2008; 473:201-209.
  10. Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation.Bone2007;40:251-264.
  11. Flier J 1998 What’s in a name?. In search of leptin’s physiologic role. J.Clinendocrinolmetab83:1407-1413.
  12. Thomas.T 2004 The complex effects of leptin on bone metabolism through multiple pathways. Curropinpharmacol 4: 295-300.
  13. Kim.G, Hong.J, Kim.S et al 2003 Leptin induces apoptosis via ERK/CPLA2/cytochrome C pathway in human bone marrow stromal cells. J. Biolchem278: 21920-21929.
  14. Martin A, David V, Malaval L et al 2007 Opposite effects of leptin on bone metabolism: a dose dependent balance related to energy intake and insulin like growth factor-1 pathway.Endocrinology148:3419-3425.
  15. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM &Karsenty 2000 Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100 197-207. (doi:10.1016/S0092-8674(00)81558-5).
  16. Wolf G 2008 Energy regulation by the skeleton. Nutrition Reviews 66 229-233. (doi:10.1111/j. 1753-4887. 2008.00027.x)
  17. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P &Karsenty G 2002 Leptin regulates bone formation via the sympathetic nervous system. Cell III 305 – 317. (doi: 10.1016/S0092-8674 (02)01049-8)
  18. Yang J, Zhang X, Wang W, Liu J. Insulin stimulates osteoblast proliferation and differentiation through ERK & PI3K in MG-63 cells. Cell biochemfunct 2010; 28: 334-341
  19. Zaida M Skeletal remodeling in health and diseases Nat Med 2007;13:791-801
  20. Mohan S, Baylink DJ. Impaired skeletal growth in mice with haplo insufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density difference. J.Endocrinol 2005; 185: 415 – 420
  21. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M et al. 2005 Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434514 – 520. (doi : 10.1038/ nature 03398)
  22. Kristensen P, Judge ME, Phim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N et al. 1998. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393 72 – 76 (doi: 10.1038/29993)
  23. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR et al. 2002 International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacological Reviews 54 161-202. (doi:10.1124/pr.54.2.161)
  24. Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME &Kunos G 1996. Inhibition of exocytotic nor adrenaline release by pre synaptic cannabinoid CB1 Receptors on peripheral sympathetic nerves.British journal of pharmacology118 2023-2028.
  25. Niederhoffer N, Schmid K &Szado B 2003. The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression. Naunyn-Schmiedeberg’sarcheives of pharmacology 367 434 – 443 (doi: 10.1007/s00210-003-0755-y)
  26. Idris AI, van’t Hof RJ, Grieg IR, Ridge SA, Baker D, Ross RA & Ralston SH 2005 Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nature Medicine 11 774-779. (doi: 10.1038/nm 1255)
  27. Ofeco, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E et al. 2006. Peripheral cannabinoid receptor, CB2, regulates bone mass. Pnas103 696 – 701(doi: 10.1073- pnas .0504187103)
  28. Matias I, Gonthier MP, Orlando P et al 2006. Regulation, Function and dysregulation of endocannabinoids in models of adipose and beta pancreatic cells and in obesity and hyperglycemia. J ClinEndocrinolMetab91:3171-3180.
  29. Di Marzo V, Goparaju SK, Wang L et al (2001) Leptin-regulated endocannabinoids are involved in maintaining food intke. Nature 410:822-825
  30. Palombaro KM. Effects of walking-only interventions on bone mineral density at various skeletal sites: a meta-analysis. J GeriatrPhysTher 2005; 28: 102-7.
  31. Ryan AS, Treuth MS, Rubin MA, Miller JP, Nicklas BJ, Landis DM, et al. Effects of strength training on bone mineral density: hormonal and bone turnover relationships. J ApplPhysiol 1994; 77: 1678-84.
  32. Kerr D, Ackland T, Maslen B, Morton A, Prince R. Resistance training over 2 years increases bone mass in calcium-replete postmenopausal women. J Bone Miner Res 2001; 16: 175-81.
  33. Sequin R, Nelson ME. The benefits of strength training for older adults. Am J Prev Med 2003; 25: 141-9
  34. Chien MY, Yang RS, Tsauo JY. Home-based trunk-strengthening exercise for osteoporotic and osteopenic postmenopausal women without fracture – a pilot study. ClinRehabil 2005; 19: 28-36.

Pathophysiology of osteoporosis in type 2 Diabetes – a multifactorial mechanism

Mrs.K.N.Poornima1, Mr.N.Karthick1  ,Dr.K.Prabhavathi2   ,Dr.A.Saravanan3

1.Tutor, Department of physiology, SRM Medical College Hospital & Research centre, Kattankulathur

2. Assistant professor, Department of physiology, SRM Medical College Hospital & Research centre, Kattankulathur

3. Professor and head, Department of physiology, SRM Medical College Hospital & Research centre, Kattankulathur