Approach

Secondary hyperparathyroidism (SHPT) is a significant disorder and is often found in patients with kidney disease, malabsorption syndromes, or inadequate exposure to sunlight. SHPT may improve with optimum medical management of the underlying condition, but if left untreated can result in significant skeletal and cardiovascular complications that contribute to overall morbidity and mortality.

Lack of sunlight-related SHPT

If inadequate exposure to sunlight is identified as a factor in vitamin D insufficiency and SHPT, advice on safe sun exposure should be given and the reasons explained. Exposure to sunlight depends on physical factors (e.g., geographic latitude, season, weather, time of day) and personal factors (e.g., skin pigmentation, body surface area exposed, sun cream use).[3][12][15] For a white person, exposure to sunlight at most latitudes for no more than 10 to 15 minutes/day between 10 a.m. and 3 p.m., on arms and legs or hands, face, and arms, during the spring, summer, and autumn, provides adequate vitamin D. Ultraviolet-B radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D.[2] Limited exposure of bare skin to sunlight should be followed by the application of a sun cream with an SPF of at least 15 to prevent damaging effects due to excessive exposure to sunlight and to prevent sun burning.

If there is concern that it may be difficult for the patient to receive sufficient ultraviolet radiation exposure, vitamin D-containing dietary supplements may be given. There are various multivitamin supplements that contain vitamin D2 (ergocalciferol) or vitamin D3 (colecalciferol). The recommended daily adequate intake of vitamin D may vary between countries and guidelines; consult local guidance.

In some countries, a number of dairy products, juice and juice drinks, and cereals are fortified with vitamin D, and their consumption should be encouraged as part of a balanced diet in people at risk of vitamin D deficiency. Similarly, if there is evidence of (or a risk of) poor dietary intake of calcium, then calcium supplements may also be appropriate in conjunction with vitamin D.

Malabsorption-related SHPT

Patients with intestinal malabsorption syndromes (e.g., Crohn's disease, Whipple's disease, cystic fibrosis, chronic pancreatitis, coeliac disease, lactose intolerance) are often vitamin D and calcium deficient. This is because they are unable to efficiently absorb the fat-soluble vitamin into the chylomicrons. This negatively impacts absorption of calcium. As the metabolic pathways in the liver and the kidneys are not compromised in these patients, the best method to correct vitamin D deficiency is to encourage sensible exposure to sunlight or ultraviolet-B-emitting light source/tanning bed.[2] This can be augmented with oral supplements of vitamin D and calcium.

Treatment of the underlying disease should also be optimised to help improve absorption. Depending on the cause, this may involve a gluten-free diet for coeliac disease, a lactose-free diet for lactose intolerance, protease and lipase supplements for pancreatic insufficiency, or corticosteroids and anti-inflammatory agents for inflammatory bowel disease.

Estimates are that the body uses an average of 3000 to 5000 international units of colecalciferol per day.[45] In the absence of adequate sun exposure, it is estimated that 1000 international units of colecalciferol are needed to maintain a healthy 25-hydroxyvitamin D level of at least 75 nanomol/L (30 nanograms/mL). One meta-analysis comparing ergocalciferol and colecalciferol has shown colecalciferol to be more effective in maintaining serum concentrations of 25-hydroxyvitamin D.[13] Dosage requirements vary for each individual, depending on the capacity of vitamin D absorption and of liver hydroxylation.[13]

Vitamin D or its analogues serve to help increase gastrointestinal calcium absorption, thereby reducing parathyroid hormone (PTH) levels. Intramuscular administration is sometimes used, as these patients have malabsorption from the gastrointestinal tract; however, this formulation is not available in the US and some other countries.

Chronic kidney disease (CKD)-related SHPT

The vast majority of patients with CKD develop SHPT at some point in the course of their disease, with the prevalence of an elevated PTH level increasing as the glomerular filtration rate (GFR) declines.[1]​​[7] Various stages of CKD have been defined as follows:[46]

  • Stage 1: Kidney damage with normal or increased GFR (greater than or equal to 90 mL/minute/1.73 m²)

  • Stage 2: Kidney damage with mild decrease in GFR (60-89 mL/minute/1.73 m²)

  • Stage 3a: Mild to moderate decrease in GFR (45-59 mL/minute/1.73 m²)

  • Stage 3b: Moderate to severe decrease in GFR (30-44 mL/minute/1.73 m²)

  • Stage 4: Severe decrease in GFR (15-29 mL/minute/1.73 m²)

  • Stage 5: Kidney failure (GFR <15 mL/minute/1.73 m² or on dialysis [stage 5D]).

In mild renal impairment, homeostatic mechanisms are recruited to maintain normal phosphorus levels, but these become increasingly inadequate in moderate to late-stage CKD. It follows, therefore, that early therapeutic intervention in this group of patients to control hyperphosphataemia and SHPT would help avert clinical (skeletal and cardiovascular) consequences of CKD-MBD.[17] However, there is a lack of data from randomised controlled trials.

The international organisation Kidney Disease: Improving Global Outcomes (KDIGO) has produced extensive guidelines for the management of bone metabolism and disease in both adults and children at various stages of CKD.[1]​​[46] The management of SHPT in patients with CKD is complex because all the variables involved (levels of calcium, phosphorus, vitamin D, PTH) affect one another. One significant unknown is in recognising the optimal time to initiate therapy and thereafter maintaining biochemical homeostasis.

Serum PTH concentrations are widely used as indicators for CKD-related SHPT and initiating therapy, but may be technically unreliable for many reasons.[47] Although the optimum PTH concentration in moderate to severe CKD is unknown, it is thought that fluctuations in PTH are clinically relevant and useful in guiding treatment. KDIGO recommends that patients with serum PTH levels that are progressively rising or persistently above the upper limit of normal, for the assay used, be evaluated for modifiable factors, including hyperphosphataemia, hypocalcaemia, high phosphate intake, and vitamin D deficiency. Treatment should not be based on a single elevated PTH value.[1]​​

KDIGO guidelines recommend lowering elevated serum calcium and phosphate concentrations towards the normal range. There is an absence of evidence supporting efforts to maintain phosphate in the normal range in non-dialysis CKD; therefore, treatment should specifically aim at lowering hyperphosphataemia and avoiding hypercalcaemia in all patients with CKD.[1]​​

The approach to managing SHPT is to optimise serum phosphorus and calcium levels through a combination of a low phosphorus diet, phosphate binders, vitamin D derivatives, and calcimimetic medications.[48]

Management of phosphate levels in CKD

  • It could be argued that phosphate binders should be initiated when PTH and fibroblast growth factor-23 (FGF-23) levels rise, as this is clearly indicative of total body phosphate retention. However, reserving treatment for hyperphosphataemia may neglect the fact that there are likely to be ongoing subclinical changes to bone metabolism with changes in serum phosphorus minimised by phosphaturia, keeping the serum phosphate concentration within the accepted normal range.[49]

  • Elevated serum levels of phosphorus should be lowered towards the normal target ranges. Dietary phosphorus should be restricted to 800 to 1000 mg/day in adults or to Dietary Reference Intake (DRI) for age when serum phosphate and plasma levels of PTH are progressively or persistently elevated above the normal reference range.[1]​​

  • Foods that contain high levels of phosphorus include dairy foods (e.g., milk, cheese, yoghurts, eggs, ice cream), some meats (e.g., liver, kidney, pate, game), fish (e.g., shellfish, kippers, whitebait, roe), some breakfast cereals (e.g., containing bran, nuts, or chocolate), biscuits/cakes (e.g., oatcakes, scones, flapjacks, rye crispbread), and miscellaneous other foods (e.g., milk chocolate, nuts, baking powder, cocoa, marzipan). Although there is evidence that SHPT can be managed with dietary phosphate and protein control, only a few studies have investigated the impact on bone disease and shown an improvement in bone and vascular health.[50][51][52][53] The impracticality with this approach is that phosphate is ubiquitous in food, it can be organic or inorganic in origin, and its content is difficult to quantify accurately. Dietary restriction also risks protein malnutrition and is particularly troublesome as patients with kidney disease are likely to have additional restrictions on salt and carbohydrate intake.[54][55][56] 

  • Serum phosphorus levels should be monitored monthly in stage 5 CKD and every 3 months in stages 3 or 4 following initiation of dietary phosphorus restriction. Hypophosphataemia should be corrected via dietary modification or enteral supplementation, or by reducing the use of phosphate binders.

  • If phosphorus or PTH levels cannot be controlled within the target range despite dietary phosphorus restriction, phosphate binders should be prescribed.[48] Either calcium-based phosphate binders, iron-based phosphate binders (e.g., iron sucrose, sucroferric oxyhydroxide), or others (e.g., sevelamer, lanthanum) are effective.[57] Calcium may not be sufficiently excreted in the context of CKD, and the use of inexpensive calcium salts as phosphate binders may render patients hypercalcaemic or in a positive calcium balance and may contribute to soft-tissue calcification.[58] Either type of binder may be used as the primary therapy in most cases. Combination of different types may be required under specialist supervision.  

  • Aluminium-based phosphate binders (e.g., aluminium hydroxide) are an alternative, but may increase the risk of adynamic bone disease due to the toxic effects of aluminium on bone.[1]​ They may be used in adolescents and adults for a single course of short-term therapy (4 weeks) if serum phosphorus levels remain severely elevated despite the use of other phosphate binders. Use of citrate-based products must be avoided in patients taking aluminium binders, as this has been shown to lead to enhanced absorption and cases of neurological toxicity.[59] After initial treatment, the aluminium-based phosphate binder should be replaced by a different phosphate binder. In patients receiving dialysis (with persistent, severely elevated phosphorus levels), the dialysis prescription should also be modified to increase dialytic phosphate removal.[59]

  • In infants and young children, calcium-based phosphate binders should be used as primary therapy; other types of phosphate binders may be used in older children.

  • In patients receiving dialysis who have severe vascular and/or other soft-tissue calcification, non-calcium-based phosphate binders are preferred.[58] Calcium-based phosphate binders should not be used in patients on dialysis who are hypercalcaemic or whose plasma PTH levels are persistently low.[1]​ The total dose of elemental calcium provided by calcium-based phosphate binders should not exceed twice the DRI for calcium based on age, and the total intake of elemental calcium (including dietary calcium) should not exceed 2500 mg/day. 

  • There is little evidence to suggest that non-calcium-based phosphate binders are superior to their calcium-containing counterparts. Indeed, the lower cost of calcium-based phosphate binders has encouraged their use for a generation. UK guidelines from the National Institute for Health and Care Excellence also recommend that adults with CKD should be offered calcium acetate as the first-line phosphate binder, and to consider a non-calcium-based binder only if they are not tolerated, hypercalcaemia develops, or PTH levels are low in those with stage 4 or 5 CKD.[60]

  • One Cochrane systematic review that assessed adults with CKD of any stage, including patients receiving dialysis, concluded that sevelamer may lower death (all causes) compared with calcium-based binders, and may induce less treatment-related hypercalcaemia in patients on dialysis. The effect of treatment with lanthanum on death and cardiovascular events, compared with calcium-based binders, remains uncertain in patients on dialysis. In CKD stages 2 to 5, sevelamer, lanthanum, iron-based, and calcium-based phosphate binders have uncertain effects on death and cardiovascular outcomes compared with placebo or usual care.[61] Further studies are required to evaluate the effects of these different phosphate binders in CKD, and to answer the question of whether phosphate binders can decrease mortality in patients with CKD compared with no treatment.

  • The OPTIMA study was an open-label, randomised study using cinacalcet to improve achievement of the Kidney Disease Outcomes Quality Initiative (KDOQI) targets (PTH 150 to 300 nanograms/L [150 to 300 picograms/mL]) in patients with end-stage renal disease. One post-hoc analysis of the study found that serum phosphorus levels in patients on dialysis with SHPT were better controlled when serum PTH levels were lowered effectively, regardless of the treatment received.[62]

Management of vitamin D deficiency in CKD

  • If plasma PTH is above the normal reference range, serum 25-hydroxyvitamin D should be measured.[1]​ Vitamin D deficiency in CKD is corrected using treatment strategies recommended for the general population.[1]​​[37] 

  • If the serum level of 25-hydroxyvitamin D is <75 nanomol/L (<30 nanograms/mL), vitamin D supplementation with ergocalciferol or colecalciferol should be initiated.[6][13][37][63]​ Vitamin D therapy should be adjusted in light of serum calcium and phosphorus levels (which should be measured at least every 3 months).[1]​ Once the patient is replete of 25-hydroxyvitamin D, continue supplementation with a vitamin D-containing multivitamin preparation or a low dose of vitamin D, and check serum levels of 25-hydroxyvitamin D annually.[15]

  • Calcifediol, a prohormone of calcitriol, is a more potent vitamin D3 supplement.[64]​ It is approved in the US for the management of SHPT in patients with CKD stages 3 to 4 and serum total 25-hydroxyvitamin D levels <75 nanomol/L (<30 nanograms/mL), and may also be available in some other countries.[65]

Management of calcium levels in CKD

  • Serum levels of corrected total calcium should be maintained within the normal range for the laboratory used.[1]​​

  • Hypocalcaemia is a classical feature of untreated CKD and contributes to the pathogenesis of SHPT. It may also develop in the context of calcimimetic treatment. Patients with hypocalcaemia should receive therapy to increase serum calcium levels if significant or symptomatic.[1]​ Therapy for hypocalcaemia should be individualised and include calcium salts such as calcium carbonate or calcium acetate orally, or calcium gluconate or calcium chloride parenterally, and/or an oral vitamin D sterol/analogue. 

  • If the corrected total serum calcium level exceeds the normal range, therapies that cause serum calcium to rise should be adjusted as follows:[1]​​

    • The use of calcium-based phosphate binders should be restricted and therapy switched to a non-calcium-based phosphate binder (e.g., sevelamer, lanthanum, or an iron-based phosphate binder)

    • The dose of vitamin D therapy should be reduced or therapy discontinued until the serum levels of corrected total calcium return to the target range.

Management of PTH levels in CKD stages 3 to 5

  • The target range for PTH in patients on dialysis is 2 to 9 times the upper limit of normal for the PTH assay.[1]​ The target range for CKD stages 3 to 5, pre-dialysis, is undefined, but severe and progressive SHPT in this group can be treated following the same principles.

  • Therapy with an active oral vitamin D sterol (calcitriol) or a synthetic vitamin D analog (e.g., doxercalciferol, paricalcitol, alfacalcidol) is indicated when modifiable factors (hyperphosphataemia, hypocalcaemia, vitamin D deficiency) have been addressed and plasma levels of PTH continue to rise towards the upper limit of the target range.[1]​​[37]​ It is suggested that the use of calcitriol and vitamin D analogues be reserved for patients with CKD stage 4 to 5, and on dialysis, with severe and progressive hyperparathyroidism.[1]​ In one multicentre, randomised trial, calcitriol and paricalcitol had equal efficacy in suppressing PTH with very few hypercalcaemic events.[66] During therapy with a vitamin D sterol/analogue, serum levels of calcium and phosphorus should be monitored at least every month after initiation of therapy for the first 3 months, then at least every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months for 6 months, and every 3 months thereafter. Dose adjustments for patients receiving vitamin D sterol/analogue therapy could be made as follows:

    • If serum levels of PTH decrease to values below the target range, vitamin D sterol/analogue therapy should be stopped until serum PTH is within the target range; treatment may then be resumed at one half of the previous dose of vitamin D sterol/analogue. If the lowest daily dose of the vitamin D sterol/analogue is being used, dosing should be reduced to alternate days.

    • If there is hypercalcaemia, vitamin D sterol/analogue therapy should be stopped until serum calcium returns to normal, and then resumed at one half of the previous dose. If the lowest daily dose of the vitamin D sterol/analogue is being used, dosing should be reduced to alternate days.

    • If there is hyperphosphataemia, vitamin D therapy should be stopped and a phosphate binder initiated, or the phosphate binder dose increased, until the level of serum phosphorus is normal, at which point the prior dose of vitamin D sterol/analogue should be resumed.

    • If serum levels of PTH fail to decrease by at least 30% after the initial 3 months of therapy, and serum levels of calcium and phosphorus are within the normal range, the dose of vitamin D sterol/analogue should be increased by 50%. Serum levels of PTH, calcium, and phosphorus must be measured monthly for 3 months thereafter.

Management of persistently high PTH levels in CKD stage 5

Calcimimetic therapy

  • Calcimimetic medications, such as cinacalcet, bind to calcium-sensing receptors (CaSR) and increase their sensitivity to extracellular ionized calcium.[67] This results in decreases in PTH, and thus calcium and phosphate levels.[63] The effect on PTH levels can be seen as quickly as 2 to 4 hours after administration.[68] Essentially, use of calcimimetics serve to reset the set point of calcium or produce a shift of the PTH-calcium curve to the right, thus loosening control over this axis.[63]

  • Calcimimetics are reserved for CKD stage 5D where a vitamin D sterol/analogue has inadequately suppressed PTH to within the target range, with or without hypercalcaemia.[69][70][71]​​ Calcimimetics can be used in combination with a vitamin D sterol/analogue.[1]​​[72]

  • There is anecdotal evidence of a reduction in fractures after starting cinacalcet therapy, but this has not been supported by bone densitometry results. A pre-specified secondary analysis in the EVOLVE trial (evaluation of cinacalcet hydrochloride therapy to lower cardiovascular events) looked at the effect of cinacalcet on fracture events in patients receiving haemodialysis. The unadjusted data showed no significant benefit; when adjusted for baseline characteristics, multiple fractures, and/or events prompting discontinuation of the study drug, cinacalcet reduced the rate of clinical fracture by 16% to 29%.[73] There are no randomised, prospective data that demonstrate improved quality of life, improvement in anaemia, reduction in phosphate binders, reduction in use of vitamin D analogues, or reduction in mortality.

  • The EVOLVE trial found that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in people with moderate-to-severe SHPT undergoing dialysis.[74] A meta-analysis, including the EVOLVE trial, showed no benefit with cinacalcet on all-cause or cardiovascular mortality.[75] [ Cochrane Clinical Answers logo ] It should be noted, however, that cinacalcet is a cytochrome P-450 inhibitor and thus can affect the metabolism of other medications. Hypocalcaemia from cinacalcet was infrequent, transient, asymptomatic, and correctable through a dose reduction.[68][76] Literature supports cinacalcet therapy to improve patient outcomes, especially with regard to vascular calcifications and presumably the very lethal condition of calciphylaxis.[77][78][79][80][81][82][83][84] Analysis of adverse events in the EVOLVE trial showed the risk of calciphylaxis was lower in the patients who received cinacalcet versus placebo.[85]

  • Etelcalcetide is a second-generation, type II calcimimetic. It is a novel D-amino acid-containing peptide agonist of CaSR and is approved for the treatment of SHPT in adult patients with CKD on haemodialysis, where treatment with a calcimimetic is indicated but cinacalcet is not tolerable or there is poor compliance.[86][87] Patients treated with etelcalcetide (administered intravenously at the end of haemodialysis) were significantly more likely to achieve the primary efficacy end point of a greater than 30% reduction in mean PTH compared with placebo.[88][89] In an active-comparator randomised controlled trial, etelcalcetide achieved its non-inferiority end point compared with cinacalcet.[90] Importantly, a higher rate of hypocalcaemia was observed for etelcalcetide compared with cinacalcet (68.9% vs. 59.8%). 

  • In the US, pharmacological therapy with calcimimetics is commonly used for SHPT in patients on dialysis.[91] Increased risk of adverse effects, including hypocalcaemia, vomiting and diarrhoea, patient compliance, and availability influence usage.[92]

Parathyroidectomy

  • It is unusual for surgery to be considered except in refractory SHPT in late-stage CKD.[41][92]​​​​ The indications for surgical intervention in SHPT are not as clear as those for primary hyperparathyroidism. Compelling reasons for surgery in this patient group include a desire to avoid cardiovascular complications (a common cause of death in patients with CKD) and severe skeletal complications.[91] 

  • Parathyroidectomy is recommended in patients with severe hyperparathyroidism (above 9 times the upper limit of normal for the assay) associated with hypercalcaemia and/or hyperphosphataemia that are refractory to medical therapy.[1]​​[92] After kidney transplantation, subtotal parathyroidectomy is the treatment of choice for patients with severe hypercalcaemia caused by persistently elevated parathyroid levels.[93] One study concluded that subtotal parathyroidectomy was superior to medical management with cinacalcet in achieving normocalcaemia (66% vs. 100%) in patients >6 months from time of transplantation.[94]

  • Parathyroidectomy for SHPT is used less frequently in the US than in the rest of the world.[95] Historically, parathyroidectomy rates initially fell with the introduction of new medical therapies for SHPT, particularly cinacalcet, but they now remain stable.[96]

  • Effective surgical therapy of severe hyperparathyroidism can be accomplished by subtotal parathyroidectomy or total parathyroidectomy with parathyroid tissue auto-transplantation.[1]​​[92] In subtotal parathyroidectomy, approximately half of the most normal-appearing gland is left behind in its anatomical position.[92] For total parathyroidectomy, all 4 glands are excised and 1 of the glands auto-transplanted in the sternocleidomastoid muscle in the neck, or in the brachioradialis muscle, or subcutaneous abdominal adipose.[91] Both methods can effectively reduce PTH levels and the ramifications of hyperparathyroidism.[92]

  • The 30-day postoperative mortality ranges from 0.8% to 3%.[92] Despite short-term risk, patients undergoing surgery actually have a reduction of long-term death with a 28% decrease in all-cause mortality and a 37% decrease in cardiovascular mortality (mean follow-up ranging from 1 to 8 years).[92] Benefits of surgery include improvements in anaemia and quality of life. 

  • The main drawback of surgery is hypoparathyroidism and the severe hypocalcaemia that may follow the acute drop in PTH level.[91] The risk of this appears to be greater in total parathyroidectomy with auto-transplantation compared with subtotal parathyroidectomy.[92]

  • In patients who undergo parathyroidectomy, in the 72 hours prior to parathyroidectomy consideration should be given to administration of a vitamin D sterol/analogue to lessen postoperative hypocalcaemia.[92][97] Preoperative levels of PTH, corrected total calcium, and total alkaline phosphatase can predict the incidence of postoperative hypocalcaemia, but careful monitoring is still required.[98]​​ Ionised calcium should be measured every 4 to 6 hours for the first 48 to 72 hours after surgery, and then twice daily until stable. If the blood levels of ionised or corrected total calcium fall below normal (i.e., <0.9 mmol/L [<3.6 mg/dL] ionised calcium corresponding to corrected total calcium of 1.8 mmol/L [7.2 mg/dL]), a calcium gluconate infusion should be initiated according to local protocols. The calcium infusion should be gradually reduced when the level of ionised calcium reaches the normal range and remains stable. When oral intake is possible, the patient should receive calcium carbonate as well as calcitriol, and these therapies should be adjusted as necessary to maintain the level of ionized calcium in the normal range. If the patient was receiving phosphate binders prior to surgery, this therapy may need to be discontinued or reduced as dictated by the levels of serum phosphorus. 

  • There is debate around the use of methylene blue as an intra-operative adjunct for the localisation of enlarged parathyroid glands; there are adverse effects associated with methylene blue, and other preoperative and intra-operative localisation methods are available. Observational evidence has suggested, however, that methylene blue was effective in identifying enlarged parathyroid glands, and its toxicity profile appeared to be mild in the absence of concomitant use of serotonin re-uptake inhibitors.[99]

  • Non-surgical options for parathyroid gland obliteration include thermal (e.g., microwave, radiofrequency, laser) and chemical (e.g., ethanol) ablation.[92][100][101]​​​ This treatment option is considered in patients who are not candidates for general anaesthesia.

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