J Bone Metab.  2020 Feb;27(1):1-13. 10.11005/jbm.2020.27.1.1.

Current Understanding of Mineral and Bone Disorders of Chronic Kidney Disease and the Scientific Grounds on the Use of Exogenous Parathyroid Hormone in Its Management

Affiliations
  • 1Institute of Musculoskeletal Sciences, Oxford University, Oxford, United Kingdom. Michael.Pazianas@ndorms.ox.ac.uk
  • 2University of Colorado Health Sciences Center, Denver, CO, USA.
  • 3Colorado Center for Bone Research, Golden, CO, USA.

Abstract

Chronic Kidney disease (CKD) disturbs mineral homeostasis leading to mineral and bone disorders (MBD). Serum calcium and phosphate (Pi) remain normal until the late stages of CKD at the expense of elevate fibroblast growth factor-23 (FGF-23), a phosphaturic hormone, followed by reduced 1,25-dihydroxy-vitamin D (1,25[OH]2D) and finally elevated parathyroid hormone (PTH). Pi retention is thought to be the initial cause of CKD-MBD. The management of MBD is a huge clinical challenge because the effectiveness of current therapeutic regimens to prevent and treat MBD is limited. An intermittent regimen of PTH, when administered at the early stages of CKD, through its phosphaturic action, could prevent FGF-23 increases, the drop of 1,25(OH)2D, and the development of renal osteodystrophy, including secondary hyperparathyroidism (HPT) and its catabolic effects on the skeleton. Even in more advanced stages of CKD that have not progressed to tertiary HPT, could be beneficial. Therapeutic effects could be achieved in vascular calcification as well. Limited experimental/clinical data support the effectiveness of PTH in CKD-MBD. Its safety, has been established only when it is used for the treatment of osteoporosis, including patients with CKD. The proposed intermittent PTH administration is biologically plausible but its effectiveness and safety has to be critically assessed in long term prospective studies in patients with CKD-MBD.

Keyword

Calcium; Chronic kidney disease-mineral and bone disorder; Fibroblast growth factor-23; Parathyroid hormone; Phosphate

MeSH Terms

Calcium
Fibroblasts
Homeostasis
Humans
Hyperparathyroidism, Secondary
Miners*
Osteoporosis
Parathyroid Hormone*
Prospective Studies
Renal Insufficiency, Chronic*
Renal Osteodystrophy
Skeleton
Therapeutic Uses
Vascular Calcification
Calcium
Parathyroid Hormone
Therapeutic Uses

Figure

  • Fig. 1 Simplified schematic presentation of the interactions of parathyroid hormone (PTH), 1,25-dihydroxy-vitamin D (1,25[OH]2D), and fibroblast growth factor-23 (FGF-23) that regulate the calcium (Ca) and phosphate (Pi) homeostasis. The parathyroid glands operate as the command center. PTH induces 1,25(OH)2D and FGF-23 production, increases Ca re-absorption and Pi excretion in the kidney and stimulates their release from bone; 1,25(OH)2D increases Ca and Pi absorption in the intestine, and FGF-23 levels, but have inhibitory effect on PTH synthesis; FGF-23, in the presence of the obligate co-receptor α-klotho, inhibits Pi reabsorption in the kidney, increases production and catabolism of 1,25(OH)2D and production and secretion of PTH. IGF-1, insulin-like growth factor 1.

  • Fig. 2 Instant min-to-min (labile calcium [Ca] pool) and bone remodeling contribution to Ca and phosphate (Pi) homeostasis. The labile pool of Ca2+ can buffer an acute Ca load as well as to maintain a stable Ca concentration during acute Ca deprivation. The magnitude of the rapid Ca exchange was estimated to be many fold higher than the daily flux from remodeling based bone turnover.[70] In postmenopausal osteoporosis, provided that the renal function is normal, the minerals released from the skeleton following the loss of bone mass, do not stretch the buffering capacity of the labile pool beyond its limits, because the kidney responds to the challenge and the blood levels of Ca, Pi, parathyroid hormone (PTH), fibroblast growth factor-23 and 1,25-dihydroxy-vitamin D remain unaffected. In bone disorders of chronic kidney disease (CKD), because of the loss of renal mass and function, it is the labile pool that is affected first, before the bone and the parathyroids (secondary hyperparathyroidism) get involved.

  • Fig. 3 Theoretical clinical advantages of intermittent administration of parathyroid hormone (PTH). FGF-23, fibroblast growth factor-23; 1,25(OH)2D, 1,25-dihydroxy-vitamin D.

  • Fig. 4 Intervention with phosphate binders and vitamin D analogues at advanced stages of chronic kidney disease (blue arrow) is the current clinical practice. We propose intermittent administration of parathyroid hormone at a much earlier stage (red arrow), soon after the first detection of elevated fibroblast growth factor-23 levels [Modified from “Forging forward with 10 burning questions on FGF23 in kidney disease.”, by Wolf M., 2010, J Am Soc Nephrol, 21, pp. 1427–1435. Copyright 2010 by the Williams & Wilkins. Modified with permission].


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