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

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

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

Normal Calcium, Phos, PTH, and Vitamin D Homeostasis

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

Calcium and Phosphate Homeostasis Bone contains an exchangeable calcium so if your serum calcium level rapidly becomes abnormal, it will normalize in 30-60 minutes (rapid buffering mechanism) Vitamin D has a lot to do with the management of these equilibria of calicum.

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

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

Vitamin D Effects on Calcium and PO4

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

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

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

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

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

When Things Start to Go Wrong

Bone and mineral disorders CKD Bone and mineral disorders

Initiation of CKD-BMD

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

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

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.

Osteitis fibrosa cystica (High Turnover Bone Disease) Elevated PTH and AlkPhos from high bone turnover Brown tumor in the distal ulna http://emedicine.medscape.com/article/392997-overview In osteitis fibrosa cystica you can see osteolytic lesions called Brown tumors that can mimic neoplastic lesions

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

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.

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

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

Why do we care about extraosseous calcification?

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

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.

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 100-450 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 100-450, but is harder to diagnose.

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 100-450

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

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

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.

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).

MKSAP QUESTIONS

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.

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

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.

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

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

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.

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

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.

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.

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.

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.

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

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

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.

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.

Initiation of CKD-BMD

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

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.

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.

Monitoring & Treatment

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

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

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

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?

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

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?

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

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?

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

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?

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

Parathyroidectomy If refractory hyperparathyroidism to all the above treatments, parathyroidectomy

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

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

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

Questions?