In SHPT, the disorder of phosphocalcic metabolism will affect the different systems of the body and manifests by specific clinical signs. Primarily bone, and then soft tissues are affected. Skin can also be affected.

In SHPT, bone remodeling and mineralization are affected.[17] Bony skeletal deformities are secondary to bone remodeling.[17] This leads to bone deformation, bone pain, and bone fractures in extreme cases. Chest wall deformity and kyphoscoliosis can be noted due to abnormal mineralization and bone remodeling.[18] Pelvic bones, hip joints, and bones of lower extremities can be deformed, and increased stress from weight-bearing can lead to fractures.[18] In children, bone deformities in SHPT can lead to rickets.[19]

Extraosseous manifestations are also seen. Calcifications affect the arterial walls, viscera, periarticular tissue, cutaneous tissue, and the eye (cornea and conjunctiva). They are thus responsible for muscle weakness, red-eye syndrome, and intense pruritus.[17] Pruritis is especially seen in advanced renal disease and is due to the deposition of calcium and phosphorus in the skin. Calcifications can occur in the heart, myocardium, Aortic, and mitral valves and can lead to increased cardiovascular events such as ischemia, left ventricular dysfunction, congestive heart failure, arrhythmias, and death.[20][21]

Calciphylaxis can be seen as ulceration of the skin, resulting from arterial obstruction, with cutaneous necrosis of the extremities.[17] Calciphylaxis is caused by high levels of PTH, calcium, and phosphorus induced by high levels of calcium in dialysate and phosphate binders.[18] In calciphylaxis, there is calcification of small arterioles and venules with severe intimal hyperplasia and can be complicated by thrombosis leading to painful skin necrosis.[18] Increased risk of infections, sepsis, and ischemia contributes to increased mortality risk in calciphylaxis.[18]

Other manifestations in SHPT include psychological, neurological, and malnutrition.[22]

Evaluation in SHPT consists of monitoring of lab values of PTH, calcium, phosphorus, vitamin D levels, and renal function.

Since, it can present as bone mineral disorder and affects the musculoskeletal system, Kidney Disease for Improving Global Outcomes (KDIGO) 2017 recommends systematically performing bone mineral density in dialysis patients with bone mineralization disorders to assess the risk of pathological fracture.[23]

There are certain striking radiological features in renal osteodystrophy. Osteosclerosis is increased bone density, especially in the axial skeleton, but bone is structurally weak and prone to stress fractures.[24] "Rugger jersey" spine sign is a hallmark sign of osteosclerosis in SHPT.[25] Osteomalacia is softening of the bone due to poor mineralization of the newly formed osteoid and is characterized by the presence of looser zones on imaging.[24] 

The brown tumor in SHPT is a lytic bone lesion caused by increased osteoclastic activity and proliferation of fibroblasts.[26] On a standard radiograph, it presents itself as a well defined hypodense lesion. These tumors are located more commonly in hands, feet, facial bones, and skull.[26] Brown tumor represents the terminal stage of bone mineral disorder in secondary hyperparathyroidism.[27] Brown tumors can be misdiagnosed as neoplasm on imaging.[27]

Osteitis fibrosa cystica is revealed on standard radiographs by subperiosteal resorption especially, at the distal phalanges, clavicles, distal ulna, and skull.[25] Cortical thinning in long bones, bone cysts, and densification of the trabecular bone are also seen.[25]

Periarticular, vascular, and more rarely, visceral metastatic calcifications can also be seen.[17] There are no clear guidelines regarding lab or diagnostic testing for vascular calcifications in SHPT.[28]

Medical Treatment

Management in SHPT targets abnormal phosphocalcic metabolism. Maintaining the serum calcium and phosphorus levels within the normal range along with control of PTH and vitamin D levels is the key in management and secondary hyperparathyroidism. The U.S. National Kidney Foundation (NKF) proposed the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and established targets for biomarkers (calcium, phosphorus, and PTH levels) to lower SHPT related mortality.[29] Also, the Kidney Disease Improving Global Outcomes (KDOGI) proposed clinical practice guidelines to address the management of CKD-MBD in dialysis patients.[29] However, most of these targets are difficult to achieve in the long term.

Phosphate binders, vitamin D, and calcimimetics have been reported in the management of calcium and phosphate levels in patients with CKD. In addition, patients are advised to restrict dietary intake of phosphorus by limiting phosphate-rich foods such as beverages, meat, cheese, and dietary products.[6] 

Phosphate binders include aluminum hydroxide, sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate.[6] Phosphate binders can be calcium-containing or calcium-free. Calcium-containing phosphate binders are known to increase vascular and soft tissue calcification and are associated with lower survival as compared to calcium-free phosphate binders.[30]

Vitamin D metabolites include cholecalciferol (1, 25 dihydroxy vitamin D3) and ergocalciferol, which is vitamin D2. Vitamin D analogs such as calcitriol, paricalcitol, alfacalcidol, and doxercalciferol are grouped under vitamin D receptor activators (VDRA) based on their site of action. Vitamin D could have a possible survival benefit in CKD patients.[31] Vitamin D analogs' use in CKD has been shown to decrease PTH levels and are likely associated with reduced inflammation, decreased tubulointerstitial fibrosis, improved endothelial function, inhibition of renin-angiotensin system, prevention of vascular calcification and decreased cardiovascular outcomes, reduced hospitalizations, and improved mortality.[31] However, the crux of these observations is from observational studies, and randomized control studies are needed to validate the outcomes.[31]

Calcimimetics are agents that increase the sensitivity of calcium-sensing receptors (CaSR) in the parathyroid gland and lead to decreased PTH production. Cinacalcet is a calcimimetic that is commercially available and extensively used in dialysis patients. Etelcalcitide is another calcimimetic. Important side effects of calcimimetics include hypocalcemia, QT prolongation, arrhythmias, worsening heart failure, and convulsions.[6][32] Calcimimetics have been shown to suppress PTH levels but do not increase calcium or phosphorus levels.[31] Cinacalcet, along with low dose vitamin D, minimizes the risk of calcification while offering the benefits of PTH lowering therapy.[33] In Evaluation of Cinacalcet Therapy to Lower Cardiovascular Outcomes (EVOLVE) study, Cinacalcet did not improve survival or cardiovascular outcomes in dialysis patients but offered significant benefits in terms of lowering PTH, calcium, phosphate, and FGF-23 levels.[32] More RCT studies are needed to explore the full range of benefits of calcimimetics.

Surgical Treatment

Parathyroidectomy is a surgical modality available if medical therapy is unsuccessful or refractory. Other indications include calciphylaxis, refractory pruritus, severe hypercalcemia (serum calcium greater than 10.2 mg/dL) or hyperphosphatemia (serum phosphorus greater than 5.5 mg/dL), anemia hyporesponsive to erythropoietin, PTH levels more than 800 pg/mL (for more than 6 months despite medical therapy) and extraskeletal calcification.[6][34] The parathyroid glands in secondary hyperparathyroidism are characterized by asymmetric enlargement and nodular hyperplasia. Assessment of parathyroid mass is an important factor in predicting the response to medical management. Glands larger than 1 cm in size or greater than 500 mm^3 ) on ultrasound represent glandular hyperplasia and are usually refractory to medical treatment.[34] It is estimated that surgery will be required in about 15% of patients in 10 years and 38% of patients in 20 years after the initiation of dialysis.[35] Following the introduction of calcimimetics, there appears to have been a reduction in parathyroidectomy rates.[34] 

Surgical techniques include subtotal parathyroidectomy and total parathyroidectomy with or without autotransplantation.[36] Subtotal parathyroidectomy involves leaving a remnant part of the gland while total parathyroidectomy removes all the glandular tissue. Sometimes, in total parathyroidectomy, small amounts of the parathyroid gland could be autografted post-surgery. There are no major differences between subtotal parathyroidectomy and total parathyroidectomy in outcomes such as complications, readmissions, 30-day mortality.[37] However, subtotal parathyroidectomy has been associated with lower extended hospital stay post-surgery and a lower incidence of postoperative hypocalcemia.[38] Subtotal hyperparathyroidism is preferred in renal transplant patients with tertiary hyperparathyroidism due to a lower risk of recurrence.[39] Total parathyroidectomy without autotransplantation is associated with a lower rate of recurrence of refractory SHPT and is preferred in patients with longer life expectancy or less likelihood of renal transplantation.[40] Total parathyroidectomy with autotransplantation is preferred for patients who cannot undergo repeat neck surgeries due to conditions such as co-existing thyroid disorders requiring surgery, history of repeated neck surgeries, recurrent laryngeal nerve injury or patients with significant perioperative comorbidities.[34]

An interesting postoperative complication of surgery is the hungry bone syndrome with the lack of osteoclastic activity causes decreased PTH, leading to hypocalcemia.[6] It can be prevented by administering high doses of calcium and using a high calcium dialysate post-surgery.[34]

Primary and tertiary hyperparathyroidism is always in the differential of secondary hyperparathyroidism. In primary hyperparathyroidism, there is increased secretion of PTH, which leads to increased calcium and phosphate levels.[41] In secondary hyperparathyroidism, there is hypocalcemia and hyperphosphatemia, which leads to increased PTH levels.[11]  In tertiary hyperparathyroidism, the PTH levels are excessively high, and the calcium and phosphorus levels are high as well.[11]

In patients on hemodialysis, Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown increased cardiovascular and all-cause mortality with calcium level greater than 10 mg/dL, phosphorus level greater than 7 mg/dL, and PTH level greater than 600 pg/ml.[42] 

Evaluation of Cinacalcet Therapy to Lower Cardiovascular Outcomes (EVOLVE) study is the largest, double-blinded, placebo-controlled clinical trial conducted in dialysis patients with SHPT. The study showed that cinacalcet therapy did not offer survival benefit or improve cardiovascular outcomes in patients on hemodialysis.[43]

In the ADVANCE study, cinacalcet with low dose vitamin D analogs as compared to flexible vitamin D dosing showed a positive trend in decreasing vascular calcification, although the study was inconclusive.[32] 

OPTIMA study is a multicenter, open-label study that showed cinacalcet based treatment algorithms were compared with conventional therapy in dialysis patients and have shown an increase in the achievement of KDOQI targets.[44]

Observational studies have shown that parathyroidectomy is beneficial in dialysis patients as it can lead to normalization of calcium and phosphorus, reduced fracture rate, improved health-related quality of life, and decreased all-cause mortality.[34] However, randomized controlled trials are lacking to validate these benefits. More prospective trials are needed to look at the outcomes of calcimimetics and parathyroidectomy.

Secondary hyperparathyroidism can have a significant impact on life due to complications such as bone and mineral disorders, cardiovascular complications, and calciphylaxis. Quality of life can be affected by symptoms such as muscle pain, bone pain, and fractures in extreme cases. Although medical therapy has been aimed to achieve target levels per Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, there is not much clinical evidence from prospective studies suggesting an improvement in survival due to vitamin D analogs or calcimimetics.[45] Calcimimetics have been shown to improve certain outcomes such as improvement in rates of parathyroidectomy, fractures, cardiovascular hospitalizations, and certain health-related quality of life parameters.[45] Parathyroidectomy is indicated in medically refractory disease. In ESRD patients on hemodialysis, the incidence of parathyroidectomy goes up with time, with about 15% of these patients undergoing surgery in 5 to 10 years from initiation of dialysis.[34] A study showed that parathyroidectomy, regardless of the technique used, significantly relieved most of the initial functional signs within seven days of the procedure, but patients continued to experience mild to moderate symptoms over a six-month follow-up.[46] Surgery and calcimimetics can offer improved survival in the initial stages of CKD resistance to standard therapy.[47] Surgery has not been shown to offer improved cardiovascular morbidity or mortality benefit in secondary hyperparathyroidism patients on hemodialysis.[47]

Secondary hyperparathyroidism is common among patients with vitamin D deficiency and chronic kidney disease. Since about half, the world population is vitamin D deficient, and about 1/7 have CKD, it is important to understand the condition in depth. Calcium, phosphorus, and vitamin D metabolism is affected in secondary hyperparathyroidism. This leads to several bone-mineralization disorders, renal osteodystrophy, and calcifications in extraosseous sites, including coronary calcifications that can lead to devastating cardiovascular outcomes and increased mortality. Thus, it is important to detect this disorder early and start therapy. Medical treatments include vitamin D analogs, calcimimetics, and phosphate binders to restore calcium, phosphorus, and PTH levels to within normal range. Early consultation with nephrologists is important to manage the outcomes. Surgery is the last option if patients do not respond to appropriate medical treatments.