Journal of Nephrology & Renal Therapy Category: Clinical Type: Review Article

Mineral Bone Disorder in Chronic Kidney Disease, Mechanics and Management

Akbar Mahmood1*
1 Department of nephrology, Sultan Qaboos University Hospital, Muscat, Oman

*Corresponding Author(s):
Akbar Mahmood
Department Of Nephrology, Sultan Qaboos University Hospital, Muscat, Oman
Tel:+968 94653356,

Received Date: May 31, 2018
Accepted Date: Jul 18, 2018
Published Date: Aug 08, 2018


Bone health is seriously affected in Chronic Kidney Disease (CKD). Subtle changes begin from the initial stages. Skeletal ill effects are related to imbalance homeostasis of four main players, calcium, phosphate, Parathyroid Hormone (PTH) and vitamin D. Their regulated action is important and interdependent for normal skeletal development, architectural integrity and strength. Dysregulation in these regulators result in progressive skeletal dystrophy if mechanism goes unnoticed which imparts extra skeletal deleterious effects with grave long term consequences in terms of bone pain, fractures, vascular, valvular and soft tissue calcification. Term renal osteodystrophy has been replaced by Mineral Bone Disorder (MBD) which include spectrum of diseases like adynamic bone disease, osteomalacia, osteitis fibrosa cystica, osteopenia and osteoporosis. Close surveillance with CKD stage appropriate investigations and timely action is crucial to detect and prevent skeletal and extra skeletal complications in order to minimize morbidity and mortality in CKD population with the outcome of improved quality adjusted life years. This article will help improve our understanding about the highly complex group of bone disorders in a practical and simplistic way with clinic-pathological correlation, diagnostic approach and evidence based management of MBD in a candid way.


Adynamic bone disease; Osteitis fibrosa cystica; Osteomalacia; Osteopenia; Osteoporosis; Mineral bone disorder


Bone disorder usually set in at the very beginning of the CKD but clinically significant features of CKD-MBD usually starts to manifest once GFR falls below 40 due to imbalance between calcium, phosphate; PTH homeostasis [1-6].

Principally bone disorders are categorized broadly based on three parameters which include Turnover, Mineralization and Volume (TMV) [7]. High and low turnover diseases are osteitis fibrosa cystica and adynamic bone disease respectively. Mineralization defective disorders are rickets, osteomalacia. Disorders affecting bone volume include osteopenia and osteoporosis. This classification system called TMV was introduced by Kidney Disease Outcomes Quality Initiative (KDIGO) in order to improve better understanding of pathological process in the bones and to adopt corrective measures [8]. Understanding of changes occurring during bone remodeling and knowledge about the causative agents is of paramount importance to detect right disease and adopt proper intervention to achieve successful outcome.


First abnormality is hyperphosphatemia which plays major role in bone remodeling. It is due to impaired tubular excretion of phosphate which triggers PTH as a compensatory response to off load body`s phosphate load without any noticeable effect during earlier stages of CKD. With progression of CKD, phosphate excretion diminishes further as it goes beyond the phosphaturic capacity of PTH with progressive rise in plasma phosphate resulting into hypocalcaemia and inhibition of calcitriol [9-11]. These changes result into secondary hyperparathyroidism [12-14] which contribute further to phosphate load due to mobilization of phosphate and calcium from the bone as a corrective attempt. Additionally proximal tubular phosphate reabsorption continues to rise due to its reduced excretion with progression of renal failure. Initial rise of PTH is beneficial in order to maintain phosphate balance, correction of hypocalcaemia and calcitriol but hyperphosphatemia over prolong period results into autonomous parathyroid gland with rising secretions as a consequence of skeletal resistance with advanced renal failure [11]. Hyperphosphatemia has direct stimulatory effect on PTH independent of calcium and calcitriol levels [15-18]. Another effect of hyperparathyroidism is high fibroblast growth factor 23(FGF 23), decrease vitamin D, Calcium Sensing Receptors (CaSR), fibroblast receptors and klotho in PTH.

FGF 23 is the main factor causing low calcitriol, not reduce nephron mass [10] as a result of inhibition of enzyme 1 alpha hydroxylase which converts 25 hydroxy vitamin D to calcitriol. FGF 23 is produced from osteocytes in response to high phosphate, calcitriol and renal injury and establish its phosphaturic effect with the help of coenzyme klotho [19] to maintain phosphate homeostasis. It`s clearance is decrease in CKD. Reduced calcitriol levels stimulate PTH [20-22] by mechanism which decrease absorption from the gut and reduce mobilization from the bones resulting into hypocalcemic state triggering PTH activation resulting in release of hormone. This phenomenon can be prevented by keeping calcitriol levels within range. An observation in a dialysis population has shown that persistent low calcitriol levels are associated with reduced vitamin D receptors within parathyroid gland which cause continuous hyper activity of the gland resulting in nodular hyperparathyroidism [23].

Calcium homeostasis is another important factor for the harmony of CKD and bone. It is maintained in a narrow range and slight disturbance result into mineral bone disorder through PTH dysregulation with grave cardio vascular consequences in terms of dysrythmias and calcifications [24,25]. Change in ionized calcium is sensed by calcium sensing receptors (CaSR) in PTH, the main regulator of calcium in the body [26]. Hypocalcemia sensed by CaSR triggers PTH to compensate this deficiency by mobilizing bone calcium by resorption [27]. CKD is usually associated with hypocalcemic state due to hyperphosphatemia, low calcitriol, and relative bone resistance to PTH. CaSR are sparse in nodular parathyroid in CKD, continuous stimulation of gland ultimately resulting into hyper phosphatemia [28-31]. High calcium phosphorous product is the basic pathology for calcifications. Worst outcome related to this abnormality is on the vasculature, especially on cardiovascular resulting into vascular and valvular calcifications [32].

Another substance which plays important role in the complex kidney bone relationship to maintain healthy equation in between is Klotho. This is a transmembrane peptide, produce from the osteocytes and acts as a cofactor for FGF23 to exert its effect [33]. Klotho continues to decrease with advancing renal failure resulting in compensatory rise of FGF23 [34,35]. Reduced klotho receptors in PTH and rising FGF 23 results into unresponsive PTH and failure of the desired outcome to suppress PTH and control phosphate balance. This situation is called skeletal resistance to PTH which contributes further to severity of secondary hyper parathyroidism. Studies have shown that high FGF 23 is associated with left ventricular hypertrophy [36] and strong association in cardiovascular morbidity and mortality outcomes in CKD [37,38]. Based on the understanding of CKD-MBD mechanism disorders of TMV becomes easier to diagnose and treat. Bone biopsy is considered gold standard for all the lesions. Bone has two important functions, maintenance of skeletal integrity and strength which is provided by cortical bone and participating in mineral homeostasis which is conferred by cancellous bone. 

Osteitis fibrosa cystica is a high turnover condition due to secondary or tertiary hyperparathyroidism. Osteoclastic activity is enhanced resulting into loss of cortical bone and end-osteal fibrosis [39]. Biochemical abnormality will result into high calcium, phosphate, Alkaline Phsophatase (ALP) and PTH. Adynamic bone disease is a low turnover state which results due to suppress PTH. Osteoid activity is suppressed and there will be loss of cancellous bone with thin osteoid [40]. This condition is associated with calcifications of vessels and soft tissues. Biochemical abnormality will result into high calcium and low ALP and PTH. 

Osteomalacia is a condition of defective mineralization of bone associated with low turnover state with markedly reduced osteocytes and osteoblasts [9,41]. Major factors predisposing this condition are hypovitaminosis D, hypo-phosphatemia and aluminum. Aluminum toxicity is not common now due to non aluminum calcium binders and improvement in water treatment techniques [42]. Biochemical abnormalities will be low calcium and phosphates and normal to high ALP or PTH.

Mix uremic osteodystrophy is a condition worth mentioning in advance CKD population, is a mixture of mix defect composed of abnormal mineralization associated with high and low turnover state. There is no clear biochemical abnormality for this specific condition. Cystic bone disease is a condition seen in dialysis population due to result of accumulation of beta amyloid protein over years. It is diagnosed by x ray or CT scan. Osteopenia is condition which is related to reduce bone volume. Certain risk factors predispose this condition which includes thin habitus, immobility, frailty, steroids and acidosis. There is no specific biochemical abnormality to suggest this condition. It is diagnosed by DEXA bone scan which is a measure of cortical bone volume, based on T score range. T score will differentiate between osteopenia and osteoporosis which is severely reduced bone density. These conditions are directly associated with higher fracture risk.

It is observed that with bone remodeling in CKD major event in the form of fracture usually occurs in dialysis population resulting in significant morbidity and mortality [9] because reaching this stage bone strength has compromised severely due to markedly reduced its mineral content and cortical strength due to high and low turnover mechanisms [39,40]. Different population studies has concluded that low turnover adynamic bone disease is much more prevalent disorder as compare to high turnover bone disorder [43,44].


Life style modification has a paramount role towards the prevention and management of bone disorders in CKD population which involves exercise, smoking cessation, reducing alcohol consumption, optimum use of calcium, vitamin D supplements and fall risk assessment and adopting preventing measures.

Hyper phosphatemia is the first culprit need to be addressed from the beginning of CKD as it is independent marker of mortality [45,46]. Aim is to keep levels within normal limits initially by patient education, dietary restrictions, later with phosphate binders, preferably non calcium based [47] and Optimization of dialysis once initiated. Refractory hyperphosphatemia to these measures is managed with holding vitamin D using calcimimetics and parathyroidectomy ultimately. These reduce intestinal phosphate absorption and PTH induced bone efflux of phosphate. Ferric citrate is another phosphate binder which has added advantage in anemia improvement [48,49].This intervention helps to control hyperparathyroidism which is the reason for osteitis fibrosa cystica. First line management of hyperparathyroidism is use of calcium, vitamin D, phosphate binders and calcimimetic. Despite optimization of these drugs if PTH levels remains beyond 800 pg/ml with skeletal dystrophic features parathyroidectomy is considered. Parathyroidectomy results in reduced fracture risks, increase bone strength, improvement in nutritional status and anemia [50,51]. A dynamic bone disease is addressed with removing Ca and vitamin D supplements from the prescription, using non calcium based phosphate binders and low calcium bath dialysate [52]. Aim is to trigger PTH secretion to help stimulate osteoblasts [42]. Teriparatide, synthetic PTH agent has come up with increase MBD in small observational studies, its use is not recommended so far [53]. Osteopenia is benefited with calcium, vitamin D preparations. Osteoporosis management is directed towards the optimization of Calcium, phosphate and PTH levels along with androgens levels and replacement as indicated [54]. Bisphosphonates orally is considered with reduced dosages. Another option is Danusomab which has been considered safe for use in CKD and dialysis population [55].


To conclude this discussion it is recommended to ensure bone health by periodic monitoring of above mentioned markers of skeletal homeostasis from the earlier stages of CKD. Keep low threshold for bone biopsy. These delineate definitive diagnosis of type of osteodystrophy and guide treatment strategy. Aim to optimize calcium, phosphate and vitamin D levels. This will modulate PTH activity regulating mineralization and strength of bony skeleton and affect bone directly by regulatory bone markers, FGF 23 and klotho. Serum renal and bone markers regulate each other in a very organized manner to maintain homeostasis. Thus bone turnover is regulated based on functioning renal reserve. Avoid over suppression of PTH by excessive use of calcium based phosphate binders, vitamin D supplements and bisphosphonates as it will result into adynamic bone which has high fracture risk incidence adding further to morbidity and mortality. Adopt appropriate approach to address causes of hyperparathyroidism, medical and surgical if adenoma. Use of cinaclacet for hyper parathyroid induced osteitis fibrosa is only indicated for dialysis population [53]. Bisphosphonates are used very cautiously in advance CKD by outweighing risks against benefits. Cost affectivity and local expertise must be taken into account while considering these management options. High index of suspicion and prompt action is the key to success for dealing CKDMBD which requires understanding of pathogenesis which is quite complex but rewarding if concept employed rightly.


  1. Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, et al. (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69: 1945-1953.
  2. Fang Y, Ginsberg C, Sugatani T, Monier-Faugere M, Malluche H, et al. (2013) Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int 85: 142-150.
  3. Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, et al. (2009) Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45: 1161-1168.
  4. Sabbagh Y, Graciolli FG, O'Brien S, Tang W, dos Reis LM, et al. (2012) Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res 27: 1757-1772.
  5. Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, et al. (2010) Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 5: 286-291.
  6. Isakova T, Wahl P, Vargas GS, Gutiérrez OM, Scialla J, et al. (2011) Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 79: 1370-1378.
  7. Moe SM, Drueke TB, Block GA, Cannata-Andia JB, Elder GJ, et al. (2009) Introduction and definition of CKD-MBD and the development of the guideline statements. Kidney Int 76: 3-130.
  8. Bakkaloglu SA, Wesseling-Perry K, Pereira RC, Gales B, Wang HJ, et al. (2010) Value of the new bone classification system in pediatric renal osteodystrophy. Clin J Am Soc Nephrol 5: 1860-1866.
  9. Hruska KA, Teitelbaum SL (1995) Renal osteodystrophy. N Engl J Med 333: 166-174.
  10. Fournier A, Morinière P, Ben Hamida F, el Esjer N, Shenovda M, et al. (1992) Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int Suppl 38: 50-61.
  11. Llach F (1995) Secondary hyperparathyroidism in renal failure: the trade-off hypothesis revisited. AmJ Kidney Dis 25: 663-679.
  12. Martin KJ, González EA (2007) Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol 18: 875-885.
  13. National Kidney Foundation (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39: 1-266.
  14. Kates DM, Sherrard DJ, Andress DL (1997) Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis 30: 809-813.
  15. Silver J, Levi R (2005) Cellular and molecular mechanisms of secondary hyperparathyroidism. Clin Nephrol 63: 119-126.
  16. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M, et al. (1996) Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 97: 2534-2540.
  17. Fine A, Cox D, Fontaine B (1993) Elevation of serum phosphate affects parathyroid hormone levels in only 50% of hemodialysis patients, which is unrelated to changes in serum calcium. J Am Soc Nephrol 3: 1947-1953.
  18. Naveh-Many T, Rahamimov R, Livni N, Silver J (1995) Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest 96: 1786-1793.
  19. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, et al. (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770-774.
  20. Hsu CH, Patel SR, Young EW, Vanholder R (1994) The biological action of calcitriol in renal failure. Kidney Int 46: 605-612.
  21. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ, Popovtzer MM (1986) Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78:1296-1301.
  22. Malluche HH, Mawad H, Koszewski NJ (2002) Update on vitamin D and its newer analogues: actions and rationale for treatment in chronic renal failure. Kidney Int 62: 367-374.
  23. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, et al. (1993) Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92: 1436-1443.
  24. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31: 607-617.
  25. Floege J, Kim J, Ireland E, Chazot C, Drueke T, et al. (2011) Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant 26: 1948-1955.
  26. Rodriguez M, Nemeth E, Martin D (2005) The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 288: 253-264.
  27. Panda DK, Miao D, Bolivar I, Li J, Huo R, et al. (2004) Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 279: 16754-16766.
  28. Gogusev J, Duchambon P, Hory B, Giovannini M, Goureau Y, et al. (1977) Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 51: 328-336.
  29. Yano S, Sugimoto T, Tsukamoto T, Chihara K, Kobayashi A, et al. (2000) Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 58: 1980-1986.
  30. Cañadillas S, Canalejo A, Santamaría R, Rodríguez ME, Estepa JC, et al. (2005) Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans. J Am Soc Nephrol 16: 2190-2197.
  31. Brown AJ, Ritter CS, Finch JL, Slatopolsky EA (1999) Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int 55: 1284-1292.
  32. Paloian NJ, Giachelli CM (2014) A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol 307: 891-900.
  33. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, et al. (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770-774.
  34. Asai O, Nakatani K, Tanaka T, Sakan H , Imura A ,et al. (2012) Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int 81: 539-547.
  35. Hu MC, Shi M, Zhang J, Quiñones H, Griffith C, et al. (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22: 124-136.
  36. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, et al. (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393-4408.
  37. Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Ha JA, Tamez H, et al. (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359: 584-592.
  38. Isakova T, Xie H, Yang W, Xie D, Anderson AH, et al. (2011) Fibroblast growth factor 23 and risks of mortality and endstage renal disease in patients with chronic kidney disease. JAMA 305: 2432-2439.
  39. Felsenberg D, Boonen S (2005) The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 27: 1-11.
  40. Malluche HH, Porter DS, Monier Faugere MC, Mawad H, Pienkowski D (2012) Differences in bone quality in low- and high-turnover renal osteodystrophy. J Am Soc Nephrol 23: 525-532.
  41. Fournier A, Morinière P, Ben Hamida F, el Esjer N, Shenovda M, et al. (1992) Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int Suppl 38: S50-S61.
  42. National Kidney Foundation (2003) K /DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42: S1-S201.
  43. Changsirikulchai S, Domrongkitchaiporn S, Sirikulchayanonta V, Ongphiphadhanakul B, Kunkitti N, et al. (2000) Renal osteodystrophy in Ramathibodi Hospital: histomorphometry and clinical correlation. J Med Assoc Thai 83: 1223-1232.
  44. D'Haese PC, Spasovski GB, Sikole A, Hutchison A, Freemont TJ, et al. (2003) A multi center study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int: 73-78.
  45. Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31: 607-617.
  46. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, et al. (2011) Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 305: 1119-1127.
  47. Ketteler M, Block GA, Evenepoel P, Fukagawa M, Herzog CA, et al. (2017) Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int 92: 26-36.
  48. Block GA, Fishbane S, Rodriguez M, Smits G, Shemesh S, et al. (2015) A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD Stages 3-5. Am J Kidney Dis 65: 728-736.
  49. Van Buren PN, Lewis JB, Dwyer JP, Greene T, Middleton J, et al. (2015) The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Pre specified Analyses of a Randomized Clinical Trial. Am J Kidney Dis 66: 479-488.
  50. Sharma J, Raggi P, Kutner N, Bailey J, Zhang R, et al. (2012) Improved long-term survival of dialysis patients after near total parathyroidectomy. J Am Coll Surg 214: 400-408.
  51. Jemcov TK, Petakov M, Bogdanovic A, Djukanovic L, Lezaic VD (2008) Parathyroidectomy and improving anemia. Arch Surg 143: 97-98.
  52. Ferreira A, Frazão JM, Monier-Faugere MC, Gil C, Galvao J, et al. (2008) Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients. J Am Soc Nephrol 19: 405-412.
  53. Cejka D, Kodras K, Bader T, Haas M (2010) Treatment of Hemodialysis-Associated Adynamic Bone Disease with Teriparatide (PTH1-34): A Pilot Study. Kidney Blood Press Res 33: 221-226.
  54. Khurana KK, Navaneethan SD, Arrigain S, Schold JD, Nally JV Jr, et al. (2014) Serum testosterone levels and mortality in men with CKD stages 3-4. Am J Kidney Dis 64: 367-374.
  55. Jamal SA, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, et al. (2011) Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res 26: 1829-1835.

Citation: Mahmood A (2018) Mineral Bone Disorder in Chronic Kidney Disease, Mechanics and Management. J Nephrol Renal Ther 4: 016.

Copyright: © 2018  Akbar Mahmood, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Herald Scholarly Open Access is a leading, internationally publishing house in the fields of Sciences. Our mission is to provide an access to knowledge globally.

© 2023, Copyrights Herald Scholarly Open Access. All Rights Reserved!