Clinical Reviews in Bone and Mineral Metabolism

, Volume 10, Issue 3, pp 174–183

Medical and Surgical Management (Including Diet)


    • Nephrology ClinicParhon University Hospital, “Gr.T. Popa” University of Medicine and Pharmacy
  • Mugurel Apetrii
    • Nephrology ClinicParhon University Hospital, “Gr.T. Popa” University of Medicine and Pharmacy
  • Eric P. Heymann
    • Renal and Transplantation UnitGuy’s Hospital, King’s Health Partners AHSC
  • David Goldsmith
    • Renal and Transplantation UnitGuy’s Hospital, King’s Health Partners AHSC
Original Paper

DOI: 10.1007/s12018-011-9116-4

Cite this article as:
Covic, A., Apetrii, M., Heymann, E.P. et al. Clinic Rev Bone Miner Metab (2012) 10: 174. doi:10.1007/s12018-011-9116-4


Considerable advances in the understanding and management of CKD–MBD were made in the last years; however, mortality rates remain extremely high, and the optimal approach for preventing and/or treating the mineral bone disorders in patients with stages 3, 4, and 5 CKD remains frustratingly unclear. In an attempt to minimize the morbidity and mortality associated with abnormal mineral metabolism, several evidence-based clinical practice guidelines were published, including the 2009 KDIGO guideline. But, because of the lack of randomized clinical trials, these guidelines were not able to generate strong statements in an area where there is a great unmet medical need for “guidance.” The current paper is a mini review of the current treatment approach of CKD–MBD, which principally involves the administration of some combination of the following: dietary phosphate restriction, phosphate binders (either calcium or non-calcium-containing binders), vitamin D (oral, injectable, or topical into PT glands), calcimimetics, parathyroidectomy/parathyroid ablation with ethanol. However, our management is driven largely by results of observational trials because the number of prospective randomized clinical trials is limited and existing clinical trials often are underpowered or use non-clinical outcomes. Future changes in care should be driven by adequately powered randomized trials with clinical end points.


Chronic kidney diseaseMineral and bone disorderHyperparathyroidismPhosphate bindersCalcimimeticsVitamin D


The optimal approach for preventing and/or treating the mineral bone disorders in patients with stages 3, 4, and 5 CKD remains frustratingly unclear despite three decades of clinical intervention. This uncertainty is related in part to a paucity of evidence around therapeutic interventions, particularly a lack of suitable randomized controlled trials (RCTs), controversies surrounding the relationship between biochemical parameters of CKD–MBD (e.g., serum calcium, phosphorus, and parathyroid hormone (PTH) levels) and specific outcomes (e.g., morbidity and mortality, vascular calcification) and whether correcting these parameters will provide any survival benefit (Table 1) [1].
Table 1

iPTH, Ca, and P target levels with various CKD classes

CKD stage





KDOQI (mg/dl)


KDOQI (mg/dl)


KDOQI (pg/ml)



Normal range for the laboratory used.

Normal range


Normal range


Normal range


Normal range for the laboratory used.

Normal range


Normal range


Normal range



Normal range


Toward the normal range


2–9 times the upper normal limit for the assay

* KDIGO working group to recommend against targets based upon absolute PTH levels

Decisions regarding treatment should be based upon trends rather than single laboratory values

Despite considerable advances in the understanding and management of CKD–MBD, however, mortality rates remain extremely high, which, if CKD–MBD were the main driver for morbidity and mortality on dialysis, is a real concern. The Dialysis Outcomes and Practice Patterns Study (DOPPS) reported that the crude 1-year mortality rates were 6.6% in Japan, 15.6% in Europe, and 21.7% in the United States [2]. So, all the nephrology societies were agreed that there was an urgent need to develop clinical practice guidelines, supported by strong recommendations for the treatment of the patients with CKD. In this context, KDIGO (Kidney Disease: Improving Global Outcomes) was established in 2003 with its stated mission to “improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines.” In 2009, KDIGO published an evidence-based clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of mineral bone disease in individuals with CKD, in an attempt to minimize the morbidity and mortality associated with abnormal mineral metabolism, abnormal bone process, and extraskeletal calcification [3].

The KDIGO document contains one of the most thorough and in-depth reviews of the available literature for CKD–MBD [3]. It is worth mentioning that many of the statements are remarkably balanced and well weighted but almost to the point of neutrality. Yet, the reality is that nephrology has the fewest randomized trials of any medical subspecialty [4], leading to a lamentably poor evidence base available to guide therapy. As a consequence, it was necessary to represent the guidance mostly as suggested actions, or recommendations, and not as instructions [3]. The majority of the recommendations presented had an evidence level C (low) or D (very low) or even no gradation, and only two of the total of forty-nine recommendations had an evidence level A (high). In other words, the authors were not able to generate strong statements in an area where there is a great unmet medical need for “guidance” [3]. As a response to the KDIGO document, several nephrology expert groups (including the ERBP group [5], but also KDOQI US [6] and the Canadian Society of Nephrology [7]) took positions in relation to KDIGO and made some comments derived from the need to adapt an international guideline to the specific conditions of each country or region. Unfortunately, successful long-term regulation of mineral metabolic parameters remains an elusive goal for many individuals on dialysis despite clinical guidelines with evidence-based recommendations [810].

The current management of mineral metabolism abnormalities in patients with CKD principally involves the administration of some combination of the following:
  • Dietary phosphate restriction

  • Phosphate binders (either calcium or non-calcium-containing binders)

  • Vitamin D (oral, injectable, or topical into PT glands)

  • Calcimimetics

  • Parathyroidectomy/Parathyroid ablation with ethanol


Phosphate retention and, later, frank hyperphosphatemia, are key contributors to CKD–MBD. Phosphate retention is an inevitable consequence of the gradual decline in renal phosphate clearance that starts at an early stage of CKD [11]. Hyperphosphatemia is, however, prevented until the later stages of CKD by two major forces that control phosphate homeostasis, PTH [12], and fibroblast growth factor-23 (FGF-23) [13].

In CKD patients, one of the main targets in managing secondary hyperparathyroidism is the prevention of a positive phosphate balance and treatment of hyperphosphatemia. The principal rationale for this is based upon the consistent observations that dietary phosphate restriction prevents hyperparathyroidism in animal models and that hyperphosphatemia is associated with increased mortality and the unequivocal animal and in vitro studies, demonstrating that phosphate is the principal factor leading to calcification of extracellular matrix. [1418].

Current clinical guidelines, therefore, emphasize the importance of normal phosphorus levels in predialysis patients, trying to restore toward normal plasma phosphate in dialysis patients [3], although these guidelines refrained from recommending specific targets. Total adult body stores of phosphorus are approximately 700 g, of which 85% is contained in bone in the form of hydroxyapatite. Of the remainder, 14% is intracellular, and only 1% is extracellular [19]. Thus, serum measurements reflect only a minor fraction of total body phosphorus and, therefore, do not accurately reflect total body stores in the setting of the abnormal homeostasis that occurs in CKD. Getting an overall measure of total body phosphate, except by immolation, is currently unachievable.

Recently, Strippoli et al. [20] published a meta-analysis using data from cohort studies of the association between serum levels of phosphorus, parathyroid hormone and calcium on the one hand and death and cardiovascular outcomes in individuals with CKD on the other hand. Overall, this was a negative meta-analysis, because the authors were unable to demonstrate any strong association between death and serum levels of parathyroid hormone and calcium in individuals with CKD. There appears to be an association only between higher serum levels of phosphorus and mortality in this population, but based on the absence of the RCTs, evidentiary basis for current clinical guideline–recommended targets of serum phosphorus remains poor [3, 21].

In addition to considering what normal serum phosphorus levels may be, it may also be useful to consider whether to start phosphate control in the early stages of CKD, when phosphate retention has begun, as shown by the elevations in PTH and FGF-23 levels. This approach should be based on any changes within the normal range and/or in the presence of other markers of phosphate retention. Apart PTH and FGF-23, Kevin et al., in a recently published paper, proposed a simple but effective tool of early phosphate retention—the measurement of the tubular reabsorption of phosphate (TRP). Thus, it would be beneficial if the interventions to limit phosphate retention begun when TRP falls below normal (<80). TRP can be easily determined by calculating the ratio of phosphate clearance to creatinine clearance [18, 22].

In this line, Block and colleagues started a randomized, double-blind, placebo-controlled pilot trial to evaluate the ability to achieve and maintain a serum phosphorus ≤3.5 mg/dL level in patients with CKD and an glomerular filtration rate (eGFR) ≥20 and ≤45 mL/min. Patients were randomized to receive three different phosphate binders (lanthanum carbonate, sevelamer carbonate, calcium acetate) with matching placebos [23]. Follow-up was 12 months, and parameters of interest are serum concentrations of FGF23, PTH, calcium, and phosphate, as well as changes in arterial stiffness (pulse wave velocity) and coronary artery calcification scores (estimated by multislice spiral CT). Data are expected to be available in autumn 2011.

Dietary Phosphate Restriction

In current clinical practice, dietary phosphate control is inconsistently prescribed in the early stages of CKD; thus, as mentioned above, it may worth to try to restrict the phosphate intake even when the serum phosphate is normal but is associated with other signs of phosphorus retention. Most clinicians recommend a maximum amount of 900 mg per day, without compromising nutritional status. Phosphate restriction should primarily include processed foods and colas and not high biologic value foods such as meat and eggs. Despite the potential usefulness of dietary intervention, it is not always practical for patients to achieve phosphate control and thus, dietary modifications alone may be unsuitable to reduce phosphorus intake sufficiently in many CKD patients.

Furthermore, in an analysis of the Third National Health and Nutrition Examination Survey (NHANES III), Kestenbaum et al. showed that serum phosphorus concentration was poorly related to dietary phosphorus intake and not related to a diverse array of phosphorus-rich foods in the general population. The authors conclude that associations of serum phosphorus concentrations with cardiovascular events were unlikely to be a result of differences in dietary intake or traditional cardiovascular risk factors [24].

Phosphate Binders

Many CKD patients require administration of oral phosphate binders (Table 2) to control serum phosphate levels, which has often been assumed to lead to improved clinical outcomes in CKD patients, despite a lack of direct evidence of clinical benefits from interventional trials. As shown in a systematic review, all phosphate binders (calcium containing and non-calcium containing) are effective in lowering phosphate binders [21]. As an example, a 2009 meta-analysis of 40 trials of phosphate binders found no significant decrease in mortality, hospitalization, or end-of-treatment calcium/phosphorus product levels with sevelamer compared with calcium-based binders [25]. Importantly, recent evidence suggests phosphate binders not only reduce phosphorus and PTH but also FGF-23 [18, 26, 27]. This may offer additional benefits, beyond simply treating secondary hyperparathyroidism, which include improvements in FGF-23–related patient outcomes, especially at earlier stages of CKD.
Table 2

List of different phosphate binders


Calcium salts




Ca Acetate

Ca Carbonate

Ca + Mg




1,334 mg with each meal (2 co)

1.5 g/day

3 tablets daily

800–1,600 mg 3 times/day with meals

1,500 mg/day

P: >5.5 to <7.5 mg/dL: 800 mg 3 times/day

P: ≥7.0 to <9.0 mg/dL: 1,200–1,600 mg 3 times/day

P: ≥9.0 mg/dL: 1,600 mg 3 times/day


2,001–2,668 mg (3–4co) with each meal NOT more than 1.5 grams Ca elemental per day

2–3 g/day NOT more than 1.5 grams Ca elemental per day

Max.12 tablets/day

Adjusted based on serum phosphorous concentration

1,500–3,000 mg; doses of up to 3,750 mg

Side effects

Nausea, vomiting, constipation, hypercalcemia

Constipation, acid rebound, nausea, vomiting, anorexia, abdominal pain, xerostomia, flatulence

Soft stools, nausea, anorexia, sensation of fullness, belching, and constipation


Nausea, vomiting, abdominal pain







Despite often being the default phosphate binder therapy, calcium salts may not always be most appropriate and should be used cautiously as they potentially cause harmful calcium retention, which may promote vascular calcification [28]. Consequently, although calcium-based and calcium-free phosphate-binding agents have similar phosphate-lowering efficacy, they have significantly different effects on serum calcium and risk of hypercalcemia.

Calcium Salts

Calcium carbonate or calcium acetate taken with meals effectively binds phosphate and limits absorption by around 50%. However, the current guideline recommendations are to avoid an excessive intake of calcium, to limit the risk of hypercalcemia with subsequent vascular calcifications. Calcium-based phosphate binders should not be used in patients with hyperphosphatemia who are also hypercalcemic. In addition, the dose of calcium-based phosphate binders should be avoided in patients with suspected adynamic bone disease, vascular calcification, and persistently low plasma PTH levels [3, 21].

Magnesium salts are also effective phosphate binders for patients who become hypercalcemic with calcium-containing phosphate binders, but they should be administered with caution in CKD patients not on dialysis because hypermagnesemia may have serious adverse effects. In patients on dialysis, magnesium carbonate (200–500 mg elemental magnesium per day) has been used successfully, with the prevention of hypermagnesemia through a reduction in dialysate magnesium concentration. The use of magnesium carbonate also allows reduction in the dose of calcium carbonate required by about half, but its use is frequently complicated by diarrhea. A solution to those problems was mixing the 2 compounds in one drug: calcium acetate and magnesium carbonate. The efficacity of the combination among dialysis patients was demonstrated in the CALMAG (CALcium acetate MAGnesium carbonate evaluation) study [29]. At the end of this controlled randomized study, CaMg was non-inferior to the comparator at controlling serum phosphorus levels and there was no change in ionized calcium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphatemia [29].


Sevelamer hydrochloride and the newer sevelamer carbonate are non-absorbable agents that contain neither calcium nor aluminum. These drugs are cationic polymers that bind phosphate through ion exchange, but the later has the advantage of not lowering serum bicarbonate.

In addition to the potential benefit of reducing the calcium load comparing with calcium-containing phosphate binders, sevelamer has some additional pleiotropic effects that may extend its basic indication. Although it appears that calcium- and non-calcium-based phosphate binders have similar effects on all-cause or cardiovascular mortality in hemodialysis patients, [30, 31], as was best shown in the Dialysis Clinical Outcomes Revisited (DCOR) trial [32], sevelamer may attenuate vascular calcification. However, it is unclear whether this benefit is associated with improvements in morbidity and mortality from cardiovascular disease. Two prospective and randomized trials—“Treat-to-Goal” and “RIND”—reported relatively less progression of coronary artery calcification with sevelamer versus calcium-containing phosphate binders [30, 33, 36]. By comparison, the Calcium Acetate Renagel Evaluation (CARE)-2 trial found similar progression of coronary artery calcification with sevelamer and calcium acetate [34], and these discordant result may be related to the higher proportion of diabetic and currently smoking patients in the CARE-2 trial, which may have leaded in a substantially greater progression of calcification independent of calcium loading. The protective effect of sevelamer on calcification may be tied to effects on serum fetuin-A levels, a protein protective against vascular calcification. A recent prospective randomized study showed that short-term (8 week) sevelamer treatment significantly increases serum fetuin-A concentration in CKD stage 4 patients. In contrast, calcium acetate had no significant effect on fetuin-A levels during the observation period [35].


Lanthanum, a rare earth element, has significant phosphate-binding properties, similar to sevelamer. Because of a high daily cost when compared to calcium-based binders, lanthanum carbonate is generally restricted to the same population of dialysis patients that now receives sevelamer. Although it seems that lanthanum accumulates in several organs in experimental studies, no significant clinical adverse effects have yet been reported with lanthanum in humans, but long-term studies are needed to confirm the safety of lanthanum administration [3741]. Lanthanum is an efficient phosphate binder, with some degree of tolerability, but like sevelamer, it is expensive.

Vitamin D

Treatment with 1,25 vitamin D or its analogs (Table 3) in predialysis and dialysis patients can reduce PTH levels but at the expense of potential increases in serum phosphorus and calcium. There are, however, insufficient prospective clinical data to determine how these effects impact on CVD and mortality outcomes in CKD patients, although observational data have suggested that vitamin D use is associated with lower PTH and improved clinical outcomes [4244]. Although 1,25D treatment can offer benefits through control of secondary hyperparathyroidism, its elevating effects on calcium and phosphorus may be associated with increased risks of calcification [4547]. It is, therefore, logical that it may be limited in those patients whose calcium or phosphorus is near the upper limit of normal to avoid potential risks of hypercalcemia and hyperphosphatemia. In addition, it is possible that increases in serum phosphorus levels stimulated by 1,25D treatment may exacerbate phosphate retention and elevated FGF-23 levels, which are potentially associated with poor patient outcomes. Concomitant therapy with phosphate binders may therefore be required. On the other hand, many studies indicate that treatment with vitamin D analogues reduces proteinuria, suppresses the renin–angiotensin–aldosterone system (RAAS), and exerts anti-inflammatory and immunomodulatory effects. These pleiotropic effects make vitamin D a potentially interesting treatment modality for renoprotection in patients with chronic kidney disease [4851].
Table 3

Different Vitamin D preparations



Adverse effect

CKD 3–5


iPHT < 600 pg/ml


iPHT > 600 pg/ml


50,000 UI/wk

Hypercalcemia: headache, nausea, vomiting, lethargy, confusion, sluggishness, abdominal pain, bone pain, polyuria, polydipsia, weakness, cardiac arrhythmias, soft tissue calcification, calciuria, and nephrocalcinosis


1,000 UI/day


0.25 μg/day

0.5–1.5 μg/HD, po/iv

1–3 μg/HD, po/iv


0.25 μg/day

0.25–1 μg/HD, po/iv

1–3 μg/HD, po/iv


2.5 μg × 3/wk

5 μg/HD po 2 μg/HD iv

5–10 μg/HD po 2–4 μg/HD iv

Paricalcitol (selective VDR activator)

1–2 μg/day

2.5–5 μg/HD iv

6–10 μg/HD iv

Less hypercalcemic than the other vitamin D products

The administration of active vitamin D analogues in predialysis is often recommended if correction of nutritional vitamin D deficiency, administration of calcium supplementation, and control of serum phosphate with diet and binders are ineffective in suppressing PTH levels. In dialysis patients with hyperparathyroidism, vitamin D is prescribed because these agents are superior to calcium supplementation alone in suppressing plasma PTH concentrations in most patients. The KDIGO guideline recommends maintaining iPTH levels in the range of approximately 2–9 times the upper reference limit for the assay [3], statement supported by the ERBP [5] and also by KDOQI commentary [6]. The PTH level range suggested in the KDIGO guideline corresponds to approximately 130-600 pg/mL, taking into account the different iPTH assays in use commercially [52]. Many observational studies reported a PTH level significantly associated with increased all-cause mortality varying from 400 to 600 pg/mL, but to date, no RCT has examined whether treatment to achieve a specific PTH target improves clinical outcomes.

Vitamin D therapy also enhances the gastrointestinal absorption of calcium and phosphate, thereby possibly resulting in an increased Ca X P product. To minimize the potential of calcitriol to increase gastrointestinal absorption of calcium and phosphate, more selective vitamin D analogues have been developed that may reduce the risk of hypercalcemia and hyperphosphatemia.

Despite some data showing an association between vitamin D and increased mortality due to calcium/phosphate abnormalities [53, 54], several studies suggest that active vitamin D analogues may have important health benefits:—a retrospective analysis of Teng et al. [55, 56] found that the use of active vitamin D analogues in incident hemodialysis patients is associated with a survival advantage compared with placebo and that the use of paricalcitol is associated with better survival than calcitriol;—Shoji et al. [57] in a retrospective study of dialysis patients also found that users of alfacalcidol versus non-users had a lower risk of death from cardiovascular disease;—and finally, a case–control study of incident hemodialysis patients reported a significantly lower risk of all-cause death and cardiovascular mortality among patients with the highest 25 vitamin D and 1,25 vitamin D levels who received active vitamin D therapy versus untreated patients with the lowest levels [58]. However, until we have a properly conducted RCT in this important area, so much of this potentially important information remains speculative and conjectural.

Percutaneous direct injection therapy of vitamin D or vitamin D analogue into parathyroid gland under ultrasonographic control has also been reported [59]. Induction of apoptosis of hyperplastic parathyroid cell and the up-regulation of vitamin D receptor on parathyroid cell by very high concentration of vitamin D at parathyroid have been proposed to explain the mechanism of the reduction in parathyroid volume [60]. The combination of these new strategies is expected to effectively and safely suppress secondary hyperparathyroidism that has been resistant to conventional medical treatments.

Refractory cases of hyperparathyroidism may be related to a loss of the vitamin D receptor (VDR) and of the calcium-sensing receptor (CaSR) rendering the parathyroid cells unable to respond appropriately to ambient calcium and/or calcitriol [6167], which eventually leads to parathyroid hyperplasia. It has been questioned whether the receptor decrease precedes hyperplasia or reduced expression is a consequence of proliferation. Some data suggest that parathyroid cell hyperplasia precedes downregulation of CaSR expression in a uremic rat model [68] and administration of vitamin D or calcimimetics resulted in a decrease in parathyroid cell proliferation associated with an elevation of both CaSR and VDR [6971].


Calcimimetics are agents that allosterically increase the sensitivity of the CaSR in the parathyroid gland (and in other organs) to calcium, augmenting the signal caused by the binding of extracellular ionized calcium to CaSR to increase intracellular calcium and decrease PTH release [72]. Cinacalcet is currently the only available calcimimetic; KDIGO recommends cinacalcet in patients with elevated or rising PTH who have serum calcium levels >8.4 mg/dL (>2.1 mmol/L). Hyperphosphatemia is not a contraindication for starting cinacalcet, unlike vitamin D analogues.

Many randomized controlled studies evaluated the effect of cinacalcet on serum PTH, calcium and phosphorus levels. In the largest reported trial (which was the combination of three phase 3 studies), 1,136 dialysis patients with secondary hyperparathyroidism were randomly assigned to traditional therapy plus cinacalcet or placebo for 26 weeks [73]. Cinacalcet plus standard therapy decreased not only serum PTH levels but also levels of calcium and phosphorus, facilitating achievement of the KDOQI targets for these parameters.

As noted above, vascular calcifications are common among patients with CKD [74, 75] being associated with cardiovascular disease and mortality among patients receiving dialysis and with a rapid progression of the disease once established [7679]. Some observational studies indicate that interventions like reducing oral calcium intake from phosphate binders [8082], or reductions in plasma PTH after parathyroidectomy (PTX), diminish the progression of vascular calcification in CKD [8386]. The potential impact of biochemical responses on the progression of established cardiovascular calcification during the treatment of sHPT with cinacalcet and low doses of vitamin D was examined in the randomized controlled trial—“ADVANCE”. Although a statistically significant difference between groups was not observed for the primary study end point (the percent change in Agatston coronary artery calcification [CAC] score from baseline to 52 weeks), differences between treatment groups were seen for CAC volume scores and for changes in Agatston and volume scores at the aortic valve. These findings thus suggest, but do not show conclusively, that treatment with cinacalcet and low doses of vitamin D sterols may attenuate the progression of established cardiovascular calcification among patients receiving hemodialysis [87].

Regarding the correlation between cinacalcet and mortality, in a recent observational study, Block et al. [88] showed that cinacalcet plus conventional therapy was associated with a significant reduction in all-cause mortality in a large cohort of hemodialysis patients. For the moment, this association cannot be translated into a relation of causality because of the observational and retrospective nature of the study. We all hope that this aspect will be soon elucidated by the ongoing RCT (Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events [EVOLVE]) [89].

Furthermore, it seems that cinacalcet not only lowers the PTH but also has an effect on bone histology, as described by Malluche et al. [90] in a prospective, double-blind, placebo-controlled trial in dialysis patients. In this study, it was demonstrated that cinacalcet lowered bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of secondary hyperparathyroidism. These encouraging results point to the need for a more robust assessment of the impact of cinacalcet on bone quality, serum markers of bone metabolism, and outcomes.


The frequency of parathyroidectomy (PTX) in CKD patients with secondary hyperparathyroidism decreased significantly in the past years, due to the utilization of medical measures that can suppress PTH secretion and to the lack of evidence showing clear superiority of PTX on meaningful clinical outcomes. Thus, KDIGO suggests PTX only in symptomatic patients with CKD stages 3–5D with severe hyperparathyroidism who fail to respond to medical/pharmacological therapy [3]. Subtotal or total PTX with autotransplant performed by an expert surgeon effectively decreases PTH, calcium and phosphorus levels. However, there is a lack of RCTs directly comparing medical with surgical therapy for hyperparathyroidism [3, 6], so the decision to perform surgery is often related to the presence of symptoms like severe hypercalcemia, progressive extraskeletal calcification or calciphylaxis, progressive and debilitating hyperparathyroid bone disease or pruritus that does not respond to medical therapy.

Three surgical procedures have been employed for the treatment of refractory hyperparathyroidism: total PTX, total PTX with autotransplantation, and subtotal PTX (Table 4). There are no RCTs comparing these three techniques, most surgeons performing either subtotal PTX or total PTX with autoimplantation. Post-surgery period may be characterized by the presence of the “hungry bone syndrome” or even increased mortality soon after the procedure is performed as with many major interventions. Even if they are no RCTs to evaluate the long-term survival after PTX, some observational studies suggest a better outcome associated with surgery, possible reasons for this including a positive impact upon cardiovascular disease and a better blood pressure control. [91]. Longer-term studies of calcifications (there is one) and bone quality post-PTX are needed.
Table 4

Different surgical approaches for the treatment of secondary hyperparathyroidism




Potential complications

Total PTX

Very good in controlling the hyperparathyroidism

The risk of persistent and/or recurrent disease is almost absent

Development of adynamic bone disease and intractable osteomalacia

Permanent hypoparathyroidism

Impaired bone healing in the absence of PTH and its anabolic effects

Need for long-term use of calcium and vitamin D

“Hungry bone” syndrome

Higher short-term mortality (as with many major interventions)

Subtotal PTX

Very good in controlling the hyperparathyroidism in the short term

Substantial risk of persistent and/or recurrent disease

Greater morbidity if repeat neck exploration is required

Total PTX with autotransplantation

Very good in controlling the hyperparathyroidism in the short term.

The ease of removing recurrent hyperplastic glands from the site of implantation under local anesthesia

Smaller risk of recurrent disease

Percutaneous ethanol injection therapy (PEIT)

Safe and simple approach

Minimally invasive intervention

Can be used in the treatment of recurrent hyperparathyroidism after subtotal parathyroidectomy

Experience with ethanol injection is limited

Transient/permanent recurrent laryngeal nerve palsy

Despite preoperative localization or intraoperative PTH monitoring and amelioration of the surgical procedures, some patients may present recurrent secondary hyperparathyroidism after subtotal PTX. These patients might be beneficiaries of the percutaneous ethanol injection therapy (PEIT) as was recently demonstrated in several studies [92, 93]. Although it represents a promising approach, larger studies are needed to evaluate the effectiveness of this treatment in controlling the recurrences of secondary hyperparathyroidism in such patients.


Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a common complication of dialysis patients, which not only contributes to the development of bone disease, but is increasingly being recognized as one of the key potential risk factors for mortality. It is, therefore, crucial to attempt to control biochemical parameters of CKD–MBD (e.g., serum calcium, phosphorus, and parathyroid hormone levels). Unfortunately, regulation of mineral metabolic parameters remains an elusive goal for many individuals on dialysis despite clinical guidelines with evidence-based recommendations [9497]. And until we know IF we can extend life (as total duration, but also just as importantly, in terms of quality) by interventions, we will not know how, when and where we should best be intervening, and this is immeasurably frustrating in 2011.

Although there have been some progress in this field, many important questions remain unresolved, including whether and how calcimimetics and vitamin D analogs should be combined or whether calcimimetics or vitamin D analogs should be preferred as a first treatment approach. It is also important to establish the optimal combination of other approaches in the treatment of mineral bone disorders (i.e., dietary phosphorus restriction, calcium-containing versus calcium-free phosphate binders, nutritional vitamin D supplementation or when and how to perform a parathyroidectomy).

It is clear that some abnormalities in mineral metabolism are associated with adverse clinical outcomes and current clinical guidelines, therefore, emphasize the importance of maintaining these parameters in the normal range or toward normal. However, our management is driven largely by results of observational trials because the number of prospective randomized clinical trials is limited and existing clinical trials often are underpowered or use non-clinical outcomes. Future changes in care should be driven by adequately powered randomized trials with clinical end points.

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© Springer Science+Business Media, LLC 2011