1. Bone and Mineral Disorders in Chronic Kidney Disease
Parker Gregg
Internal Medicine R3

3. Learning Objectives
Describe the mechanisms by which bone and mineral disorders develop in CKD
Differentiate secondary hyperparathyroidism, adynamic bone disease, and other bone/mineral disorders by lab values and clinical presentation
List 3 different medications for the treatment of hyperparathyroidism in CKD and how they differ

4. Table of Contents
Review of normal calcium, phos, PTH, and vitamin D homeostasis
How things go so wrong in CKD
MKSAP cases to illustrate types of bone and mineral disorders in CKD
Monitoring and treatment of bone and mineral disorders in CKD

5. Normal Calcium, Phos, PTH, and Vitamin D Homeostasis

6. Key Points ECF calcium comes from guts, bones, and kidneys
Vitamin D’s main goal is to increase bone mineralization
PTH does everything it can to increase ECF calcium, but to keep phos relatively balanced it wastes phos in the urine
ECF calcium and vitamin D decrease PTH secretion; phos increases PTH secretion

7. Calcium and Phosphate Homeostasis
Bone contains an exchangeable calcium so if your serum calcium level rapidly becomes abnormal, it will normalize in minutes (rapid buffering mechanism)
Vitamin D has a lot to do with the management of these equilibria of calicum.

8. Key Points ECF calcium comes from guts, bones, and kidneys
Vitamin D’s main goal is to increase bone mineralization
PTH does everything it can to increase ECF calcium, but to keep phos relatively balanced it wastes phos in the urine
ECF calcium and vitamin D decrease PTH secretion; phos increases PTH secretion

9. Vitamin D Metabolism PTH Cholecalciferol (D3) Liver
25-hydroxycholecalciferol
Kidney
Activation
PTH
1,25-dihydroxycholecalciferol
Check 25-OH vit D level to assess for nutritional deficiency
Inhibition
Gut
Increased intestinal absorption of calcium

10. Vitamin D Effects on Calcium and PO4

11. Key Points ECF calcium comes from guts, bones, and kidneys
Vitamin D’s main goal is to increase bone mineralization
PTH does everything it can to increase ECF calcium, but to keep phos relatively balanced it wastes phos in the urine
ECF calcium and vitamin D decrease PTH secretion; phos increases PTH secretion

12. PTH Effects on Calcium and PO4
Calcium and PO4 via increased production of
vitamin D
Calcium and PO4
PTH diminishes proximal tubule reabsorption of phos while increasing renal tubular absorption of calcium in the distal tubules and collecting ducts.
Does everything it can to increase calcium in the extracellular fluid but maintains more stable phos by dumping it in the urine
Calcium
PO4

13. Key Points ECF calcium comes from guts, bones, and kidneys
Vitamin D’s main goal is to increase bone mineralization
PTH does everything it can to increase ECF calcium, but to keep phos relatively balanced it wastes phos in the urine
ECF calcium and vitamin D decrease PTH secretion; phos increases PTH secretion

14. Parathyroid Hormone Regulation
Parathyroid gland
High calcium and 1,25-OH vit D decrease PTH secretion
High phos stimulates PTH Ca
Vit D
Increased in response to: Low calcium, High phosphate, Decrease in 1,25-OH vit D
Suppressed by: High calcium, High 1,25-OH vit D, FGF-23
PO4

15. Key Points ECF calcium comes from guts, bones, and kidneys
Vitamin D’s main goal is to increase bone mineralization
PTH does everything it can to increase ECF calcium, but to keep phos relatively balanced it wastes phos in the urine
ECF calcium and vitamin D decrease PTH secretion; phos increases PTH secretion

16. When Things Start to Go Wrong

17. Bone and mineral disorders
CKD
Bone and mineral disorders

18. Initiation of CKD-BMD

19. Decreased filtration of phos
Initiation of CKD-BMD
Decreased GFR
Early secondary hyperparathyroidism maintains normal calcium and phos levels
Decreased filtration of phos
Hyperphosphatemia
Hypocalcemia develops from hyperphosphatemia and from decreased 1,25-OH vit D synthesis in CKD
In patients with stages 2-3 CKD, increased PTH helps maintain the serum calcium level. However, once patients get to stage 3 CKD, they demonstrate transient post-prandial hyperphosphatemia and hypocalcemia, starting the increase in PTH that ultimately leads to sustained hyperphosphatemia in later CKD.
Hypocalcemia
Increased PTH

20. Secondary Hyperparathyroidism
Calcium and PO4 via increased production of
vitamin D
Calcium and PO4
PTH can only waste so much phos, so eventually the GFR decreases to a point that PTH isn’t able to adequately lose phos anymore. Then all the PTH around just increases bone resorption and makes hyperphosphatemia worse. It can also cause hypercalcemia.
In the meantime, PTH has a decreased effect on the kidney so patients get deficient of 1,25-OH vit D, causing hypocalcemia. Hypocalcemia + low vitamin D + high phos all stimulate PTH production.
Secondary hyperparathyroidism affects almost all patients with CKD.
Calcium
PO4

21. Osteitis fibrosa cystica (High Turnover Bone Disease)
Elevated PTH and AlkPhos from high bone turnover
Radiographic sclerosis, cystic bone lesions, and subperiosteal bone resorption
Subperiosteal bone reabsorption, characteristic cystic bone lesions
Loss of cortical bone, leading to decreased bone strength.

22. Osteitis fibrosa cystica (High Turnover Bone Disease)
Elevated PTH and AlkPhos from high bone turnover
Brown tumor in the distal ulna
In osteitis fibrosa cystica you can see osteolytic lesions called Brown tumors that can mimic neoplastic lesions

23. Tertiary Hyperparathyroidism
Parathyroid hyperplasia that no longer responds to calcium
Autonomous secretion of PTH
Hyperplastic gland doesn’t involute

24. Secondary Hyperparathyroidism (High Turnover Bone Disease)
Undersuppression of PTH
Oversuppression of PTH
Secondary Hyperparathyroidism
(High Turnover Bone Disease)
Adynamic Bone Disease
(Low Turnover Bone Disease)
Typically seen with PTH <100, but can be seen with PTH as high as 450.

25. PTH Effects on Calcium and PO4
Calcium and PO4 via increased production of
vitamin D
Calcium and PO4
In adynamic bone disease, oversuppression of PTH or oversupplementation of vitamin D or vitamin D analogs leads to mostly normal mineralization of abnormal bone. Osteoblasts don’t make normal collagen. You see loss of cancellous bone (at the end of long bones, with high surface area [many trabeculations] and responsible for the maintenance of ECF calcium and phos), leading to worsened homeostasis, hypercalcemia, and increased vascular/soft tissue calcification.
Calcium
PO4

26. Adynamic Bone Disease (Low Turnover Bone Disease)
Bone Pain
Fractures
Low Bone Turnover
Bone pain from inability to repair microdamage
Fractures
Hypercalcemia from reduced bone uptake of calcium after a meal, and from calcium based phos binders
Vascular calcification
Hypercalcemia
Vascular Calcification

27. Why do we care about extraosseous calcification?

28. Extraosseous Calcification
Vascular Calcification
Increased Mortality
Use of vit D analogs and Ca supplements can lead to hypercalcemia -> increased Ca-PO4 product leads to increased medial vascular calcification -> decreased vascular compliance -> may increase cardiovascular mortality

29. Adynamic Bone Disease (Low Turnover Bone Disease)
The most common bone disease in dialysis patients, particularly diabetics, and one of the leading causes of bone disease in stage 3-5 CKD.

30. Adynamic Bone Disease (Low Turnover Bone Disease)
Caused by oversuppression of PTH
Therefore…
PTH is
Bone specific AlkPhos is
LOW*
Gold standard for diagnosis is bone biopsy, but this is rarely done. PTH <100 + low bone specific alk phos make this diagnosis. PTH can have adynamic bone disease.
Excess use of vitamin D supplements and/or calcium causes functional hypoparathyroidism
Can also occur s/p parathyroidectomy
LOW/NORMAL
*PTH <100. Can see in patients with PTH , but is harder to diagnose.

31. Secondary Hyperpara-thyroidism
Lab Values in CKD-BMD
Disorder
Phos
Calcium
PTH
AlkPhos
Secondary Hyperpara-thyroidism
Adynamic Bone Disease    
−/
−/
−/ *
*Adynamic bone disease not excluded in PTH

32. Profound hypocalcemia
Osteomalacia
Vitamin D deficiency
Profound hypocalcemia
Characterized by abnormal mineralization and increased unmineralized osteoid (different from adynamic bone disease because the osteoblasts are still making osteoid)
Aluminum exposure

33. High or low turnover bone disease
Mixed Osteodystrophy
Osteomalacia
High or low turnover bone disease
Either high or low turnover and abnormal mineralization.

34. B2-Microglobulin Amyloidosis (Dialysis-Related Amyloidosis)
B2 microglobulin proteins normally cleared by the kidneys accumulate to 15-60x the normal levels and deposit in the periarticular structures and joints.

35. B2-Microglobulin Amyloidosis (Dialysis-Related Amyloidosis)
Amyloid deposits in joints/periarticular structures leading to carpal tunnel syndrome, spondyloarthropathies, hemarthrosis, joint pain, immobility. Late in the disease can have systemic deposition (esp heart, GI tract). Leads to cystic bone lesions and pathologic fractures.
Doesn’t cause a lot of mortality, but does cause significant morbidity for patients on long term dialysis (especially hemodialysis).

36. MKSAP QUESTIONS

37. MKSAP Question 1
A 59 year-old woman is evaluated for a 2-week history of right hip pain. She has chronic kidney disease treated with peritoneal dialysis. Medications are epoetin alfa, calcium acetate, calcitriol, and a multivitamin. She has no history of exposure to aluminum-containing medications. On physical examination, vital signs are normal. There is tenderness over the right lateral trochanter. Internal and external rotation of the hip elicit pain.

38. MKSAP Question 1
Laboratory studies: Phosphorus 5.6 mg/dL Calcium 10.2 mg/dL Alkaline phosphatase 86 U/L Intact PTH 21 pg/mL 1,25-dihydroxyvitamin D 52 pg/mL 25-hydroxyvitamin D 15 ng/mL

39. MKSAP Question 1
Plain radiograph of the right hip shows diffuse osteopenia. An area of lucency is seen along the medial aspect of the femoral neck on the right side consistent with a stress fracture.

40. MKSAP Question 1
Which of the following is most likely the cause of this patient’s bone disease?
Adynamic bone disease
B2-Microglobulin-associated amyloidosis
Osteitis fibrosa cystica
Osteomalacia

41. MKSAP Question 1
Osteopenia, fracture, bone pain, serum PTH level <100 pg/mL, and normal AlkPhos level are consistent with adynamic bone disease, which is a leading cause of bone disorders in patients with stage 5 CKD. Risk factors: advanced age, DM, poor nutrition, and oversuppression of PTH with therapeutic agents

42. MKSAP Question 1
This patient’s 1,25-dihydroxyvitamin D level >30 pg/mL is consistent with repletion of vitamin D stores with calcitriol. The relatively low 25-hydroxyvitamin D level may be caused by reduced cutaneous synthesis and decreased dietary intake. Decreased hepatic 25-hydroxylation also may occur in patients with CKD.

43. MKSAP Question 1
Osteitis fibrosa cystica: hyperphosphatemia, hypocalcemia, and 1,25-vitD deficiency -> stimulate PTH secretion -> increase bone turnover. Radiographic sclerosis and subperiosteal bone resorption, elevated PTH, elevated AlkPhos

44. MKSAP Question 1
B2-microglobulin-associated amyloidosis: cystic bone lesion at the end of long bones that can enlarge over time, resulting in pathologic fractures Osteomalacia: uncommon. Usually after exposure to aluminum-containing phosphate binders. Usually have elevated serum PTH.

45. Take Home Point
Adynamic bone disease is a major cause of bone disease in patients with stage 5 CKD and usually manifests as osteopenia, fractures, and bone pain accompanied by a serum PTH level below 100 pg/mL and a normal alkaline phosphatase level.

46. MKSAP Question 2
A 33 year-old woman comes for follow up examination for a left fibula fracture due to a fall 1 week ago. She has hypertension and stage 5 CKD treated with home hemodialysis. Medications are lisinopril, sevelamer, epoetin alfa, paricalcitol, and kidney vitamins.

47. MKSAP Question 2
On physical examination, temperature is normal, blood pressure is 130/70 mmHg, pulse rate is 88/min, and respiration rate is 12/min. BMI is 29. Cardiopulmonary exam is normal. An arteriovenous fistula is present in the left forearm. Except for a cast on her left leg, musculoskeletal examination is normal and reveals no bone pain.

48. MKSAP Question 2
Laboratory studies: Hemoglobin 10.3 g/dL Albumin 3.5 g/dL Phosphorus 5.8 mg/dL Calcium 8.4 mg/dL Parathyroid hormone 700 pg/mL Alkaline phosphatase 330 U/L

49. MKSAP Question 2
Which of the following is the most likely cause of this patient’s bone disease?
Adynamic bone disease
Avascular necrosis
Osteoporosis
Secondary hyperparathyroidism

50. MKSAP Question 2
CKD is associated with progressive alterations in mineral and bone metabolism that can cause bone disease. In patients with ESRD, the kidney’s inability to excrete phosphorus leads to hyperphosphatemia. Loss of kidney function also is associated with 1,25-vitD deficiency. Hyperphosphatemia along with decreased 1,25-vitD levels result in hypocalcemia, which leads to direct stimulation of PTH secretion.

51. MKSAP Question 2
Furthermore, decreased 1,25-vitD levels cause increased production of PTH. Therefore, bone disease due to secondary hyperparathyroidism, the most common bone pathologic finding seen in patients with ESRD, develops. This patient’s hyperphosphatemia, hypocalcemia, and elevated serum PTH and AlkPhos are consistent with secondary hyperparathyroidism.

52. Initiation of CKD-BMD

53. MKSAP Question 2
Adynamic bone disease: hypoparathyroidism caused by excess vitamin D intake and/or calcium loading Osteoporosis: low bone mass, associated with reduced bone strength and increased risk of fractures. Does not affect the concentrations of serum calcium, phosphorus, or AlkPhos

54. MKSAP Question 2
Avascular necrosis: transient or permanent lack of blood supply to bone, causing death of bone and bone marrow infarction that results in mechanical failure. Typically present with chronic bone pain and not fracture.

55. Take Home Point
Bone disease due to secondary hyperparathyroidism commonly occurs in patients with ESRD and may be associated with elevated serum PTH and alkaline phosphatase levels, hyperphosphatemia, and hypocalcemia.

56. Monitoring & Treatment

57. Monitoring (KDOQI Guidelines)
Serum Ca and Phos
PTH
Vitamin D
Alkaline Phosphatase
Stage 3
Q 6-12 months
At least annually
Yearly, replete as needed --
Stage 4
Q 3-6 months
Yearly
Stage 5
Q 1-3 months

58. 54 y/o M with stage 3 CKD Ca PO4 PTH Initial Presentation 8.2 5.8 43
FIRST INTERVENTION?

59. Phosphate Restriction
Low phosphate, low potassium. Avoid processed foods, cokes, meat, eggs, dairy.

60. 54 y/o M with stage 3 CKD Ca PO4 PTH Initial Presentation 8.2 5.8 43
6 Months Later
7.8
5.7 50
You try dietary phosphate restriction for 6 months, but it doesn’t work. What’s your next step in therapy?
WHAT’S NEXT?

61. Phos Binders Calcium Phos Binders: Non-Calcium Phos Binders:
Calcium Carbonate (Tums)
Calcium Acetate (Phoslo)
Non-Calcium Phos Binders:
Sevelamer (Renagel, Renvela)
Lanthanum (PhosRenal)
Less used:
Aluminum Hydroxide
Magnesium Hydroxide
Niacin
Renagel is in an HCl salt; Renvela is in an HCO3 salt
Long term aluminum use will cause dementia, osteomalacia, and microcytic anemia

62. WHAT’S ELSE DO YOU CHECK?
54 y/o M with stage 3 CKD Ca
PO4
PTH
Initial Presentation
8.2
5.8 43
6 Months Later
7.8
5.7
106
WHAT’S ELSE DO YOU CHECK?

63. Vitamin D Analogs Nutritional deficiency
Cholecalciferol or ergocalciferol
Cholecalciferol (vit D3) for 25-OH vit D <30
Ergocalciferol (vit D2) for 25-OH vit D <20
Oral active vit D derivatives for elevated PTH despite phos binder plus ergocalciferol for 6 months (contraindicated in hypercalcemia)
Calcitriol (1,25-diOH vit D) – can get hypercalcemic
Paracalcitol (Zemplar) and other syntetic vitamin D analogs (usually not given to pre-dialysis patients). Act only at the parathyroid gland and doesn’t act on the gut to increase Ca absorption

64. 54 y/o M with stage 4 CKD Ca PO4 PTH Initial Presentation 8.2 5.8 43
6 Months Later
7.8
5.7
106
1 Year Later
7.0
6.5
648
WHAT’S NEXT?

65. Vitamin D Analogs Nutritional deficiency
Cholecalciferol or ergocalciferol
If PTH still elevated with phos binder and vit D supplementation…
Cholecalciferol (vit D3) for 25-OH vit D <30
Ergocalciferol (vit D2) for 25-OH vit D <20
Oral active vit D derivatives for elevated PTH despite phos binder plus ergocalciferol for 6 months (contraindicated in hypercalcemia)
Calcitriol (1,25-diOH vit D) – can get hypercalcemic
Paracalcitol (Zemplar) and other syntetic vitamin D analogs (usually not given to pre-dialysis patients). Act only at the parathyroid gland and doesn’t act on the gut to increase Ca absorption
Switch to active vitamin D derivatives:
Calcitriol (1,25-dihydroxyvitamin D)
Paracalcitol (Zemplar) with dialysis

66. 54 y/o M with stage 4 CKD Ca PO4 PTH Initial Presentation 8.2 5.8 43
6 Months Later
7.8
5.7
106
1 Year Later
7.0
6.5
648
7.5
5.0
700
WHAT’S NEXT?

67. Cinacalcet (Sensipar)
Calcimimetic Therapy
Cinacalcet (Sensipar)
Cinacalcet (Sensipar): calcium analog that acts only on the calcium receptor of the parathyroid gland (usually not given to pre-dialysis patients). Can cause hypocalcemia
Does not act on the GI tract to increase absorption of calcium

68. Parathyroidectomy
If refractory hyperparathyroidism to all the above treatments, parathyroidectomy

69. Treatment of Adynamic Bone Disease
STAHP!!
Allow PTH secretion to rise
Decrease serum calcium
Allow PTH secretion to rise (decrease calcium phos binders, add non-calcium phos binders, stop vitamin D analogs, use low dialysate Ca concentration)
Stop vitamin D analogs
Switch to non-calcium phos binders

70. Learning Objectives
Describe the mechanisms by which bone and mineral disorders develop in CKD
Differentiate secondary hyperparathyroidism, adynamic bone disease, and other bone/mineral disorders by lab values and clinical presentation
List 3 different medications for the treatment of hyperparathyroidism in CKD and how they differ

71. You (yes, you!) can reason through how CKD-BMD happens
Take Home Points
You (yes, you!) can reason through how CKD-BMD happens
Secondary hyperparathyroidism is the end result of the natural progression of the abnormalities set in motion by hyperphosphatemia
Adynamic Bone disease is common, and it is caused by oversuppression of PTH
Phos binders, vitamin D analogs, and calcium analogs are all used to treat hyperparathyroidism

72. Questions?