Renal Osteodystrophy

Etiology

Renal osteodystrophy is invariably seen in patients of chronic kidney disease, although the disease processes may differ in patients. Histologically, there is a classification into high or low bone turnover states. 

High bone turnover states: They lead to increased rates of bone resorption and formation. Increased parathyroid hormone (PTH) levels play a major role in the pathogenesis of high bone turnover states. Hyperparathyroidism can be primary, secondary, or tertiary. Neoplasms of the parathyroid glands secreting PTH autonomously, an example of tertiary hyperparathyroidism, can lead to a high bone turnover state. 

Secondary hyperparathyroidism is the predominant cause of osteodystrophy. The different factors involved in the pathway building up to secondary hyperparathyroidism are also worth mentioning in the etiology of renal osteodystrophy:

• Phosphate retention: High phosphate levels in the blood can stimulate PTH secretion in more ways than one. It can either directly increase PTH mRNA levels or decrease the levels of calcium and calcitriol, indirectly causing a surge in PTH levels.[1][3]
• Calcium: The relationship between calcium and PTH levels is well established. A decrease in serum calcium will also stimulate PTH secretion.
• Role of calcitriol: Calcitriol and PTH both increase serum calcium levels, and in cases of decreased calcitriol in the body, secondary hyperparathyroidism ensues due to decreased calcium absorption through the intestine and a reflex increase in PTH. Calcitriol is also required for suppressing PTH secretion by the parathyroid glands. 
• Fibroblast growth factor 23: FGF-23 is responsible for decreasing phosphate levels in the body, and a decrease in FGF-23 can lead to secondary hyperparathyroidism. 

The predominant histological bone pattern in renal osteodystrophy is osteitis fibrosa, which is a product of high bone turnover due to secondary hyperparathyroidism. Along with the PTH level, secondary factors that play a role in the development of osteitis fibrosa include interleukins 1, 6, and TNF-alpha.[4]

Low bone turnover states: Diseases included here are mainly osteomalacia and dynamic bone disease, both seen in patients with end-stage renal disease (ESRD). The important factors that play a role in the pathogenesis are:

Osteomalacia: Heavy metal intoxication, mainly aluminum, can lead to dysfunction of both osteoblasts and osteoclasts. A defect in bone mineralization due to the dysfunctional osteoblast leads to an excess of accumulated bone matrix. Other metals implicated include iron and cadmium. 

Adynamic bone disease (ABD): The pathogenesis of adynamic bone disease mainly revolves around the suppression of PTH, leading to low bone turnover and inadequate bone mineralization but no accumulation of excess osteoid in contrast to osteomalacia. Factors which lead to this include:[5][6]

• Calcium and vitamin D: Aggressive treatment with these in patients of chronic kidney disease (CKD) causes a chronic suppression of PTH. 
• Continuous ambulatory peritoneal dialysis (CAPD): This leads to a large influx of calcium into the body through the dialysate. 
• Diabetes mellitus: Evidence suggests that elevated glucose and decreased insulin levels together suppress PTH secretion.[7]
• Other factors: Interleukin 4 and a deficiency of osteogenic-protein 1 play secondary roles in the pathogenesis of ABD.[4]

Mixed uremic osteodystrophy includes components of the high turnover osteitis fibrosa and low turnover mineralization defects, as seen in osteomalacia.[3]

Epidemiology

In the last couple of decades, dynamic bone disease has become the most prominent subtype of renal osteodystrophy seen in patients undergoing dialysis. Earlier, the aluminum-induced low bone turnover disease was frequently seen before the advent of aluminum-free dialysate solutions and the use of non-aluminum phosphate binders.[1] 

The overall trend has also shifted from hyperparathyroidism induced high bone turnover diseases to adynamic bone disease.[8] Various factors have been hypothesized to have caused this. The overuse of vitamin D analogs that cause suppression of PTH is one of them.[9] Calcium-containing phosphate binders also have a similar mechanism.

Pathophysiology

It is important to understand the ongoing bone remodeling that takes place and the elements involved in it to get a more complete picture of the pathophysiology of renal osteodystrophy. The two main cells in this process are osteoclasts that cut down or resorb the bone and osteoblasts that build-up or form new bone.[10] Osteoblasts produce the organic matrix of the bone consisting of type 1 collagen along with other non-collagenous proteins like alkaline phosphatase and osteocalcin.[11]

The process begins with the resorption of bone by the osteoclasts, which are activated by osteoblasts through a RANK-RANK ligand complex and intricately regulated by several factors like PTH, vitamin D, osteoprotegerin (OPG), etc. In reality, this complex first activates osteoclasts precursor cells, which in turn provoke the gene transcription by nuclear factor kappa B leading to an increase in osteoclasts and bone resorption. 

Factors that stimulate the complex and aim to increase osteoclasts formation are PTH, vitamin D, and acidosis. Interleukins like IL-1,6, tumor necrosis factor, and MIF-1 alpha also activate osteoclasts. This will increase serum calcium levels by increasing bone resorption. Osteoprotegerin is an osteoclastogenesis inhibitory factor and ultimately decrease bone resorption.[12] 

The derangement in the levels of these factors mentioned, especially PTH, is the culprit in renal osteodystrophy. Patients suffering from chronic kidney disease (CKD) have an accelerated disease process due to the alteration in levels of other factors like phosphate, calcium, and vitamin D along with PTH. High bone turnover states involving an increased PTH act through the RANK complex to activate more osteoclasts. On the other hand, low bone turnover states have lower than normal PTH levels, which renders the bone incapable of integrating calcium into the new bone that is being formed.

History and Physical

It is not uncommon for patients with renal osteodystrophy to be asymptomatic, although some may present with bone pain or fractures. Low turnover states leading to defective mineralization and the inability to repair any ongoing damage, are more commonly symptomatic. This is seen in patients with adynamic bone disease who have bone pain as the predominant symptom.[13] The higher incidence of fractures in these patients can also be attributed to the poor structural integrity of the bones in patients with ABD. Proximal muscle and axial skeleton involvement point towards aluminum toxicity and the resulting osteomalacia.[14]

Patients with ABD are likely to have an overly-suppressed PTH along with an inability to buffer calcium onto the bone leading to hypercalcemia.[15] Vascular calcifications are an important complication and can lead to site-specific manifestations. Blood vessel calcifications can increase wall stiffness and pulse pressure, along with chronic hypertension. This could result in a higher incidence of cardiovascular events, stroke, and is an important cause of mortality in CKD patients.[16]

Evaluation

As most patients with renal osteodystrophy are asymptomatic, investigations should be performed only in cases with a high degree of suspicion. Although a bone biopsy is the gold standard for diagnosis, this is not always feasible in clinical medicine. Blood tests for markers of bone metabolism coupled with radiological imaging, can help to narrow down the differentials in these patients:

• Parathyroid hormone - PTH plays a major role in the pathogenesis of renal osteodystrophy, and it can be used to distinguish between high and low bone turnover states.[4] The cut-off level for PTH to make a diagnosis varies depending on whether the patient is currently on dialysis or not. If PTH levels are elevated, a reasonable next step is to evaluate the levels of vitamin D in the blood. 
• Bone-specific alkaline phosphatase - bsALP is an indicator of osteoblastic activity. Low levels of bsALP can suggest a low bone turnover disease. bsALP or ALP can be combined with PTH to help establish the diagnosis. 
• Osteocalcin and propeptide of type I collagen [PICP] - These markers of bone formation can be found in the blood of patients with osteodystrophy, but studies have shown a poor association between the markers and the disease, hence they are not used frequently in clinical practice.[1]

Radiological evidence - Hyperparathyroidism resulting in osteitis fibrosa leads to skeletal changes, which can be evidence of underlying renal osteodystrophy. Subperiosteal resorption, endosteal resorption, and osteolysis can be seen in the skull, clavicle, or the distal phalanges. A dual-energy X-ray absorptiometry (DEXA) scan can be used to measure bone mineral density, although studies have not shown this to be very useful.[17]

The only confirmatory test is a bone biopsy followed by double tetracycline labeling, which can also accurately pinpoint the histological pattern of bone disease in the patient.[5]

Treatment / Management

The treatment of renal osteodystrophy revolves around the strict control of phosphate, calcium, vitamin D, and PTH. The components of a management plan in cases of high bone turnover diseases with an elevated PTH are:

Vitamin D: If blood levels of vitamin D are <30 ng/ml, a 20,000 U/day supplementation of vitamin D2 is recommended. This will lead to a suppression of PTH and, in turn, of osteoblasts. Vitamin D analogs should not be used in adynamic bone disease. These analogs could lead to hypercalcemia, depending on their potencies. Calcitriol, being the most potent, holds the highest risk of hypercalcemia along with the added risk of hyperphosphatemia that is seen to some degree with all vitamin D analogs, and hence, recommendations are to withhold these if the serum phosphate is more than 5.5 mg/dL.[18] Paricalcitol and falecalcitriol are some of the other vitamin D analogs that are being put to use.(A1)

Cinacalcet: This is used to lower PTH levels by improving the calcium-sensing receptor sensitivity in the parathyroid glands. When used along with the other components of the treatment regimen of renal osteodystrophy, it has proven to help achieve PTH level targets in patients on dialysis.[19](A1)

Phosphate: To suppress the elevated PTH levels, maintaining a serum phosphate below 5.5 mg/dL is essential. A phosphorous restricted diet is strongly recommended, with a vegetarian meal preferred due to the low bioavailability of phosphorous in vegetarian protein.[20] Phosphate binders taken along with meals is the step-up intervention to maintain the recommended phosphate levels. Non-calcium containing binders like sevelamer and lanthanum are preferred as they do not change the calcium levels. However, in cases of hypocalcemia where a need to supplement calcium arises, calcium-containing binders like calcium acetate and calcium carbonate can be prescribed. In these situations, elemental calcium intake should be limited to <2 g/day.[18](A1)

Calcium: The level of calcium is kept near the high end of the normal range by modifying the concentration of calcium in the dialysate. This is done to keep the PTH suppressed and to decrease the calcium and phosphorus (Ca X P) product. 

Acidosis: Acidosis is seen in many patients and should be managed using sodium bicarbonate. 

Parathyroidectomy: Cases with severe hyperparathyroidism along hypercalcemia and hyperphosphatemia, or hyperparathyroidism refractory to medical treatment are indications for a surgical consult. A total parathyroidectomy could lead to over suppression of PTH and eventually to adynamic bone disease. Subtotal parathyroidectomy is preferred over total parathyroidectomy. 

Aluminum: If aluminum-induced osteomalacia is suspected, chelation with desferrioxamine can be initiated. 

A different approach is taken in patients with low bone turnover diseases: 

An attempt to prevent the suppression of PTH is made by decreasing the calcium and vitamin D levels. The use of non-calcium containing binders will maintain phosphate levels without increasing those of calcium and subsequently prevent the suppression of PTH. This has proven to increase the rate of bone formation.[21] The concentration of calcium in the dialysate is also kept lower than the standard dialysate for similar reasons. The benefits of stopping or restricting vitamin D intake are still uncertain.(A1)

Differential Diagnosis

A patient presenting with signs and symptoms of bone disease or structural deformities is evaluated using PTH, alkaline phosphatase, calcium, and phosphate levels. Although a history of CKD or ESRD can effectively establish the diagnosis, other bone diseases should be ruled out:

• Osteopenia
• Osteomalacia
• Osteoporosis
• Vitamin D resistant rickets
• Osteopetrosis
• Paget's disease

Prognosis

Complete recovery from renal osteodystrophy is possible only with a renal transplant. While evaluating the overall prognosis of this condition, other factors like the bone-vascular axis should be taken into account. Vascular calcifications, arteriosclerosis of blood vessels, and the subsequent cardiovascular events in patients of renal osteodystrophy are all a part of this axis, which is vital in determining the outcome for any patient with this condition.[22]

Complications

Renal osteodystrophy itself is a complication of end-stage renal disease. Once osteodystrophy sets in, patients will present most commonly with fractures due to excessive action of PTH or due to inadequate mineralization of bone seen in adynamic bone disease. Bone pain is a common symptom, too, along with skeletal deformities and growth retardation in children. 

The pathophysiology of previously reported cases of carpal tunnel syndrome in patients of renal osteodystrophy undergoing dialysis has been under debate. The nerve dysfunction seen in carpal tunnel syndrome does not seem to have a clear association with underlying osteodystrophy.[23]

Studies have also suggested that patients who suffer from renal osteodystrophy and had an initial fragility fracture have a higher probability of suffering from cardiovascular events and metastatic calcification.[24]

Other complications like septic arthritis, tendon ruptures, and osteonecrosis may also be seen.