Table 1.

Most common causes of secondary hyperparathyroidism.

Cause of secondary hyperparathyroidism	Proposed intervention thresholds	Comments
Vitamin D deficiency	Aim for 25(OH)D concentrations of 30 ng/mL (75 nmol/L) to avoid secondary hyperparathyroidism	Re-test PTH when vitamin D replete. PTH concentrations may remain elevated for 6–12 months and optimization of calcium intake is mandatory (31)
Low-dietary calcium intake	1200 mg/day recommended for postmenopausal women, 1000 mg/day for men 51–70 years, and 1200 mg/day for older men (32)	Evaluate calcium intake using a dietary questionnaire. Patients should increase calcium intake or use calcium supplements
Hypercalciuria due to renal abnormalities	Urinary calcium excretion >250 mg/24-h (6.25 mmol/24-h) in females, >300 mg/24-h (7.5 mmol/24-h) in males, or >4 mg/kg/24-h (0.1 mmol/kg/24-h) (33, 34)	‘Thiazide challenge’ test (administer hydrochlorothiazide 25 mg twice a day for 2 weeks; check PTH levels prior to starting thiazide and after 2 weeks of therapy). PTH normalization supports renal secondary causes of PHPT (35)
Renal insufficiency	eGFR <60 mL/min/1.73 m2 (36, 37)	As kidney function declines, 1α-hydroxylation activity decreases and, consequently, active vitamin D levels fall, calcium levels decline, and PTH levels increase (36, 37)
Gastrointestinal disorders associated with calcium malabsorption	Celiac disease, inflammatory bowel disease, and bariatric surgery (38, 39, 40, 41)	Measure anti-tissue transglutaminase antibodies and fecal calprotectin to consider celiac disease and inflammatory bowel disease, respectively (39, 40)
Medications	Diuretics (42, 43), lithium, anticonvulsants (44, 45), bisphosphonates (46, 47), denosumab (48, 49), SGLT2 inhibitors (50, 51, 52), and proton pump inhibitors (53)	Non-thiazide diuretics can increase PTH levels (42, 43). If possible, discontinue and reevaluate PTH. Lithium therapy can raise PTH levels (44, 45). However, the decision to withdraw from therapy in these patients is difficult and should be made by a psychiatrist. Treatment with bisphosphonates or denosumab can raise PTH levels as a result of positive calcium signaling to the parathyroid glands in the context of inhibited bone resorption (7, 46, 47, 49). Bisphosphonate effects may last for a long time after discontinuation (54). Denosumab discontinuation should be avoided to prevent excessive bone loss. Recent studies showed that SGLT2 inhibitors have complex interactions with bone metabolism, including an increase in PTH (50, 51, 52)
Phosphate metabolism disorders	Hyperphosphatemia and FGF-23-mediated hypophosphatemia are both associated with secondary hyperparathyroidism (55, 56, 57)	Extracellular phosphate regulation involves changes in PTH levels. Both high and low phosphate levels may be associated with secondary hyperparathyroidism (56, 57, 58)

25(OH)D, 25-hydroxyvitamin D; eGFR, estimated glomerular filtration rate; FGF-23, fibroblast growth factor 23; PTH, parathyroid hormone; SGLT2 inhibitors, sodium-glucose cotransporter-2 inhibitors.