Secondary Hyperparathyroidism and Renal Bone Disease: A Growing Problem in the Older Adult

At the conclusion of this activity, participants should be able to: 1. Recognize the prevalence and implications of chronic kidney disease and secondary hyperparathyroidism in the aging population in the United States. 2. Describe the pathophysiology of secondary hyperparathyroidism. 3. Understand the importance of recognition and proper management of the various forms of renal bone disease. 4. Explain the available medical and surgical treatments for patients with secondary hyperparathyroidism, including novel therapies like cinacalcet. ____________________________________________________________________________________________________________________________ The population of persons with end-stage renal disease (ESRD) is increasing in the United States. There are more than 20 million Americans with chronic kidney disease (CKD), with 300,000 people on hemodialysis. The number of these patients is estimated to double by the year 2010.1,2  The average age of the patient undergoing dialysis in the United States has been steadily increasing over the last several decades and will likely increase as the population continues to age. In 2000, for example, the average age was approximately 62 years.3 Among the common complications seen in persons with CKD, particularly in those on longterm hemodialysis, is secondary hyperparathyroidism. This affects one in four patients receiving hemodialysis.4 This review will address the pathophysiology of secondary hyperparathyroidism and current approaches to its management and possible prevention. CASE PRESENTATION Ms. JK is a 51-year-old female with a history of ESRD, on hemodialysis for 15 years, osteoporosis, cardiac arrest status post-automatic implantable cardiac defibrillator placement, who now presents with nausea, vomiting, diarrhea, inability to eat for the past 7 days, and crampy abdominal pain. She also complains of hip and back pain. This is one of many admissions for similar symptoms. Laboratory data are significant for parathyroid hormone (PTH) > 2500 pg/mL, calcium 11.3 mg/dL, phosphorus 10.9 mg/dL, and 1,25-dihydroxyvitamin D 5.0 pg/mL. Abdominal x-ray demonstrates diffuse vascular calcifications and severe renal bone disease. Electrocardiogram is significant only for shortened QT interval. PATHOPHYSIOLOGY Secondary hyperparathyroidism is a common problem in patients with CKD that results from the physiologic response of the parathyroid glands to attempt to maintain calcium homeostasis in the face of hypocalcemia, diminished 1,25-dihydroxyvitamin D levels, and hyperphosphatemia. Secondary hyperparathyroidism is characterized by persistently elevated PTH levels and various disturbances in bone and mineral metabolism.5,6,7 Tertiary hyperparathyroidism can occur when prolonged hypocalcemia leads to parathyroid gland hyperplasia and autonomous oversecretion of PTH by the parathyroid gland with resultant hypercalcemia. Hyperphosphatemia is believed to be the main initiating factor of PTH release by inducing hypocalcemia and decreasing production of 1,25- dihydroxyvitamin D by the kidneys, which is usually already low due to renal impairment. Although phosphate retention starts when the glomerular filtration rate (GFR) decreases to less than 60 mL/min, it only becomes a problem when GFR decreases below 25 mL/min.8 As a result of hyperphosphatemia, there is an increase in the calciumphosphorus product leading to metastatic calcification and calcium phosphate precipitation in arteries, joints, soft tissues, and viscera. This phenomenon has been observed when the calcium-phosphorus product is more than 72-80 mg2/dL2. Calciphylaxis is a much more severe form of metastatic calcification, with involvement of small- and medium-sized dermal arteries and the potential for ischemic necrosis. For this reason, the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend maintaining the calcium-phosphorus product 55 mg2/dL2 in stage 3-5 CKD.8,9 The regulation of parathyroid gland function and secretion of PTH is controlled by three molecular targets on parathyroid gland cells. A calcium-sensing receptor (CaSR) on the surface of the parathyroid gland chief cells senses changes in the serum calcium level and functions as the major regulator of PTH secretion.10 CaSR is activated by an increase in serum calcium with a consequent reduction of PTH secretion, while hypocalcemia leads to a decrease in CaSR activity and an increase in PTH secretion. In addition to CaSR, there is a vitamin D receptor, the action site for 1,25-dihydroxyvitamin D, and a putative extracellular phosphate sensor.11 Renal bone disease is the most recognized complication of secondary hyperparathyroidism. In ESRD, hypocalcemia leads to higher-than-normal PTH levels in an attempt to maintain a normal serum calcium concentration. In addition, there is evidence that uremia, disturbed vitamin D metabolism, hyperphosphatemia, and acidosis all lead to a resistance to PTH action and, consequently, a further elevation of PTH levels.12 The overall incidence of hip fractures in the dialysis population is 17.4 times greater than in the general population, with most fractures occurring in those with adynamic bone disease (ABD), as described below.13 In addition to the effects of chronic renal disease on calcium, phosphorus, and secondary hyperparathyroidism, metabolic acidosis itself contributes to renal osteodystrophy. Bone carbonate, released to buffer hydrogen ions, leads to a release of calcium from the bone and a decrease in bone calcium stores.  There are several forms of renal bone disease: • Osteitis fibrosa cystica: Bone turnover is increased due to secondary hyperparathyroidism and elevated serum PTH levels. Features include woven osteoid bone produced in response to excess PTH.12 Prevalence of this bone disease has fortunately decreased, due to the common use of 1,25- dihydroxyvitamin D and calcium binders in the management of patients with ESRD. • Osteomalacia: Bone turnover is reduced with increased volume of unmineralized bone. This disease most commonly resulted from aluminum intoxication from aluminum-containing phosphate binders and, many years ago, to aluminum content in dialysate. Osteomalacia secondary to aluminum is uncommon now, and the incidence has dramatically decreased. Osteomalacia develops most commonly in patients with 25-hydroxyvitamin D deficiency in the absence of underlying renal disease and 1,25-dihydroxyvitamin D deficiency in those persons with renal disease who have low levels and are not on supplementation. • Adynamic bone disease: Bone turnover is low due to suppressed PTH secretion, with intact PTH level usually being below 100 pg/mL. There is an increasing prevalence of this condition due, in part, to maintenance of PTH levels at normal levels in individuals with ESRD. ABD is characterized by decreased bone formation and cellular activity without an increase in osteoid thickness.12  Risk for fracture is greater in patients with lower serum PTH levels than in the patients with higher PTH levels.13 • “Hungry bone” syndrome: Commonly seen after parathyroidectomy. It is believed that correction of secondary hyperparathyroidism leads to increased bone formation and decreased bone resorption, and thus is characterized by a rapid fall in plasma calcium, phosphorus, and magnesium levels post-surgery, which may lead to tetany and seizures. There is also the possibility of bone fractures. MEDICAL MANAGEMENT Several agents are available for the medical management of secondary hyperparathyroidism (Table I). Phosphorus binders are the mainstay of treatment for hyperphosphatemia, as dietary phosphorus restriction is usually not sufficient to lower serum phosphorus enough to prevent hypocalcemia and consequent increased PTH levels. Most effective when taken with meals, these agents act by helping to absorb phosphorus contained with food. Those phosphorus binders that contain calcium not only bind phosphorus but can increase serum calcium levels at the same time, increasing the risk of possible hypercalcemia.4 The most common calciumcontaining phosphorus binders used in the United States are calcium carbonate and calcium acetate. Sevelamer is a calcium- and aluminum-free cationic exchange. It does not lead to hypercalcemia and, in addition, has been found to lower low-density lipoprotein levels. The high price of sevelamer precludes its routine use. Aluminum hydroxide was the phosphate binder of choice for many years, but it is now rarely used due to serious adverse effects from systemically absorbed aluminum, including dementia, bone and muscular pain, and microcytic anemia. Sometimes, in resistant cases, aluminum hydroxide can be used for a short-term therapy of no longer than 4 weeks at a time. Vitamin D in the form of 1,25-dihydroxyvitamin D (calcitriol) is another modality used to treat secondary hyperparathyroidism. Circulating vitamin D levels diminish when GFR falls below 40 mL/min. Since adequate kidney function must be present to convert the less active 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, only the active form of vitamin D must be used.4 Prior to initiating treatment, it is recommended that a serum 25-hydroxyvitamin D level be measured and replacement started if the level is less than 30 ng/mL. Vitamin D should not be used in patients with hyperphosphatemia, as it can cause a further increase in serum phosphorus. Calcitriol can be administered either orally or intravenously, and both routes are equivalent in their ability to suppress PTH. Since all vitamin D products can lead to hypercalcemia and hyperphosphatemia, vitamin D3 (cholecalciferol) should not be used in people with ESRD if plasma calcium is more than 9.5 mg/dL or plasma phosphorus is more than 5.5 mg/dL.8 Cinacalcet hydrochloride is a calcimimetic agent acting as a calcium receptor agonist. It has recently been approved by the Food and Drug Administration for treatment of secondary hyperparathyroidism in patients with CKD, and also for treatment of hypercalcemia in patients with parathyroid cancer. Cinacalcet acts on the CaSR, which is a member of the G protein-coupled receptor superfamily, which senses extracellular calcium, and then transmits a second messenger signal to induce compensatory physiologic responses by regulating secretion of PTH.4,10,14 Calcimimetic agents increase the sensitivity of the CaSR to extracellular calcium ion, thus inhibiting the release of PTH. They can lower serum PTH levels within several hours of administration.5 This action is different from vitamin D sterols, which diminish transcription of the PTH gene and hormone synthesis over a period of many hours or several days.5 Cinacalcet hydrochloride represents the first calcimimetic agent that provides clinicians with a treatment option for decreasing PTH levels while simultaneously decreasing values of calcium and phosphorus and the calcium-phosphorus product.15 Trials indicate that use of cinacalcet resulted in approximately 41% of patients attaining intact PTH (150-300 pg/mL) and calcium-phosphorus ( 55 mg2/dL2) values recommended by KDOQI guidelines, as compared with less than 10% achieving optimal control in the group treated with phosphate binders and vitamin D analogs alone.14,16,17 The recommended starting dose is 30 mg once daily, which can then be titrated in 30-mg increments based on the patient’s needs. The maximum recommended dose is 180 mg per day. The dose should not be changed more frequently than every 2-4 weeks.1,18 Cinacalcet is generally safe and well tolerated, with nausea and vomiting being the most common side effects. The frequency of nausea is unrelated to the dose of cinacalcet, whereas vomiting occurs more frequently at higher doses.1,5,15 Asymptomatic hypocalcemia is another commonly reported side effect and can be prevented by not starting cinacalcet if serum calcium concentration is below 8.4 mg/dL. If hypocalcemia does occur, it can be successfully managed with vitamin D sterols and calcium-containing phosphate binders.1,4,5 The drug is only approved for the management of secondary hyperparathyroidism in the hemodialysis population and stage 5 CKD. It is not approved for the predialysis population due to the risk of hypocalcemia, which can lead to QT interval prolongation or seizures by lowering seizure threshold, especially in patients with a known seizure disorder.4,10 SURGICAL MANAGEMENT There are several indications for surgical management of secondary hyperparathyroidism (Table II). Parathyroidectomy is an option for patients with severe symptomatic renal bone disease due to secondary hyperparathyroidism with very high intact serum PTH levels (of more than 800 pg/mL) or in those with severe hypercalcemia, hyperphosphatemia, or elevated calcium-phosphorus product that is resistant to medical therapy. Surgical management may also be considered for those patients who have developed autonomous PTH secretion and hypercalcemia, or so-called tertiary hyperparathyroidism. Several surgical procedures are available: subtotal parathyroidectomy, total parathyroidectomy with auto transplantation of parathyroid tissue, or total parathyroidectomy without auto transplantation.19 Total parathyroidectomy without auto transplantation is not recommended, as it can lead to the development of permanent hypoparathyroidism, ABD, impaired bone healing in the absence of PTH and its anabolic effects, and the need for a long-term calcium and vitamin D supplementation.20 There is no clear opinion as to which surgical modality is superior since there are no randomized clinical trials comparing different surgical procedures: subtotal versus total with auto transplantation to brachioradialis muscle, sternocleidomastoideus muscle, or abdominal fat. In patients who have had total parathyroidectomy with auto transplantation, if there is recurrence of hyperparathyroidism, removal of parathyroid tissue from the auto transplantation site under local anesthesia is easier to perform and safer than repeat neck exploration, as would be required in patients who had subtotal parathyroidectomy. In some centers, percutaneous ultrasoundguided ethanol injections into parathyroid tissue are also used. Ethanol is injected using ultrasound guidance into the largest gland. PTH is measured 1 week later, and if it continues to be above 200 pg/mL, another gland is identified and the procedure is repeated. This procedure remains experimental only, due to a risk of a transient or permanent damage to the recurrent laryngeal nerve.21 OUTCOME OF THE CASE PATIENT Ms. JK was diagnosed as having tertiary hyperparathyroidism and severe renal bone disease. She underwent sestamibi parathyroid scan, which revealed four-gland hyperplasia. Subsequently, subtotal parathyroidectomy was performed, with development postoperatively of hypocalcemia due to so-called “Hungry bone” syndrome. Initially, she was managed with calcium supplements. On followup 6 months later, she continued to do well. Currently, Ms. JK is undergoing hemodialysis 3 times a week, and there is slight improvement in her renal bone disease. CONCLUSION Secondary hyperparathyroidism and its skeletal complications is a growing problem as the number of persons with CKD continues to increase. There is no age limitation for starting hemodialysis in the United States. Consequently, a greater number of older persons are being treated than ever before with increased risk of comorbidities, especially secondary hyperparathyroidism and its associated complications. The physician should not only recognize the signs and symptoms of secondary hyperparathyroidism but anticipate it and initiate preventive therapy in a timely manner, as prevention is the best approach in this situation. Most patients can be adequately managed with phosphate binders and vitamin D analogs. In those patients on dialysis with stage 5 CKD and who have significantly elevated PTH level and worsening of calcium-phosphorus product, the calcimimetic agent cinacalcet provides a novel therapeutic approach for controlling secondary hyperparathyroidism by directly targeting the molecular mechanism that regulates the secretion of PTH.