Bone and mineral metabolism

1. What is chronic kidney disease–mineral and bone disorder (CKD-MBD)?

CKD-MBD is a systemic disorder of mineral and bone metabolism resulting from CKD that may be manifested by either one or a combination of the following:

• Laboratory abnormalities associated with disturbed mineral metabolism, including abnormalities of:

  • Calcium

  • Phosphorus,

  • Parathyroid hormone (PTH)

  • Vitamin D metabolites

• Bone disease defined as renal osteodystrophy (ROD) including abnormalities in:

  • Bone turnover

  • Bone mineralization

  • Bone volume

  • Bone strength

  • Linear growth

• Calcification of extraskeletal tissue, which would include the vasculature and other soft tissues

2. How do we define ROD?

ROD is the term used to describe the bone lesions associated with CKD-MBD. ROD is an alteration of bone morphology in patients with CKD. It represents the skeletal component of the systemic disorder CKD-MBD. It is assessed by bone histomorphometry. There are three key histologic descriptors:

• Bone turnover: normal, increased, or decreased

• Bone mineralization: normal or abnormal

• Bone volume: normal, increased, or decreased

This is referred to as the TMV (turnover, mineralization, and volume) system—with any combination of each of the descriptors possible in each specimen. The TMV classification scheme provides a clinically relevant description of the underlying bone pathology.

3. Name the factors contributing to secondary hyperparathyroidism and high-turnover bone disease.

The factors responsible for secondary hyperparathyroidism associated with CKD include:

• Hyperphosphatemia from diminished kidney phosphorus excretion

• Hypocalcemia, impaired kidney production of active 1,25-dihydroxyvitamin D (calcitriol)

• Alterations in the control of PTH gene transcription

• Skeletal resistance to the calcemic action of PTH

• Fibroblastic growth factor 23 (FGF23), which may indirectly promote hyperparathyroidism by inhibiting production of 1,25-dihydroxyvitamin D

4. Describe the bone lesion associated with hyperparathyroidism.

The primary histologic bone lesion associated with moderate to severe hyperparathyroidism is a high-turnover lesion, sometimes called osteitis fibrosa cystica . Clinically it is associated with nonspecific bone pain, proximal myopathy. The serum-intact PTH level is usually higher than 350 to 500 pg/mL. Radiologic features are subperiosteal resorption, Brown tumors, and a mottled and granular salt-and-pepper appearance to the skull. The histologic features include:

• Increased turnover (T) as indicated by increased bone resorption and formation with increased numbers of osteoclasts and osteoblasts, and increased tetracycline uptake

• Abnormal mineralization (M), as indicated by increase of woven bone, peritrabecular fibrosis and there may or may not be increased osteoid

• Generally increased volume (V)

5. How is high-turnover bone disease treated?

Treatment of this disorder entails prevention and correction of the factors leading to secondary hyperparathyroidism:

• Phosphorus control: dietary restriction, phosphate binders, adequate dialysis

• Prevention of hypocalcemia: oral calcium supplements, correction of vitamin D deficiency, dialysis

• Suppression of PTH production and secretion: vitamin D receptor activators (VDRA), including calcitriol, paricalcitol, and doxercalciferol, and/or the use of calcimimetics (cinacalcet, elecalcetide; Table 20.1 )

  Table 20.1.

  Impact and Challenges With Vitamin D to Treat Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease

  VITAMIN D COMPOUND	BIOLOGIC AND CLINICAL IMPACT	CHALLENGES
  Ergocalciferol (D 2 ) Cholecalciferol (D 3 )	Effective in repleting 25-D and 1,25-D in patients with early-stage CKD and adequate kidney function	Requires activation in the liver to generate 25-D Requires activation in the kidney to generate active 1,25-D Provides only partial suppression of PTH in patients with later-stage CKD
  ER Calcifediol	Effective in repleting 25-D and 1,25-D in patients with CKD 3 and 4 Effectively suppresses SHPT	No data in CKD stage 5
  Calcitriol	Biologically active VDR agonist Effectively suppresses SHPT Reduces abnormal high bone turnover	Hypercalcemia, hypercalciuria, and hyperphosphatemia evident at high doses
  Doxercalciferol	Suppresses SHPT similar to or better than calcitriol Noted reduction in serum bone-specific alkaline phosphatase and osteocalcin	Requires activation in liver to generate active 1,25-D Induces significant elevation of serum P, elevating need for phosphate binder use
  Alphacalcidol	Suppresses SHPT similar to or better than calcitriol	Requires activation in kidney to generate active 1,25-D Induces significant elevation of serum P, elevating need for phosphate binder use
  Paricalcitol	Biologically active VDR agonist Effectively suppresses SHPT Noted reduction in serum bone-specific alkaline phosphatase and osteocalcin	Minimal elevation in Ca, P, and Ca × P product, requiring Ca and P monitoring

  1,25-D , 1,25-Dihydroxyvitamin D; 25-D , 25-hydroxyvitamin; Ca , calcium; CKD , chronic kidney disease; ER , extended release; P , phosphorus; PTH , parathyroid hormone; SHPT , Secondary hyperparathyroidism; VDR , vitamin D receptor.

• Surgical parathyroidectomy: in severe cases, parathyroidectomy may be required; however, bone biopsy should be considered prior to surgery