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Metabolic Bone Disorders Bone Involvement in Primary Hyperparathyroidism and Changes After Parathyroidectomy Lars Rolighed, MD, 1 Lars Rejnmark, PhD, DMSci 2 and Peer Christiansen, DMSci 3 1. Senior Resident, Department of Surgery P; 2. Consultant, Department of Endocrinology and Internal Medicine; 3. Professor and Consultant, Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark Abstract Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands and has primary effects on kidney and bone. During the pathologic growth of one or more parathyroid glands, the plasma level of PTH increases and causes primary hyperparathyroidism (PHPT). This disease is normally characterized by hyperparathyroid hypercalcemia. In PHPT a continuously elevated PTH stimulates the kidney and bone causing a condition with high bone turnover, elevated plasma calcium, and increased fracture risk. If bone resorption is not followed by a balanced formation of new bone, irreversible bone loss may occur in these patients. Medical treatment can help to minimize the loss of bone but the cure of PHPT is by parathyroidectomy. After operation, bone mineral density increases during the return to normal bone metabolism. Supplementation with calcium and vitamin D after operation may improve the normalization to normal bone metabolism with a secondary reduction in fracture risk. Keywords Primary hyperparathyroidism, bone mineral density, parathyroidectomy, vitamin D, PTH, calcium, bone remodeling, fracture Disclosure: The authors have no conflicts of interest to declare. Received: September 2, 2013 Accepted: November 28, 2013 Citation: US Endocrinology 2013;9(2):181–4 Correspondence: Lars Rolighed, MD, Department of Surgery P, Aarhus University Hospital, Tage Hansens Gade 2, 8000 Aarhus C, Denmark. E: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia with a constantly elevated or inappropriately high plasma concentration of parathyroid hormone (PTH). This hormone, an 84 amino-acid peptide synthesized in the parathyroid glands, is the major regulator of calcium homeostasis and exerts its effects mainly on kidney and bone, where the PTH 1 receptor is expressed. 1 This membrane-bound receptor is activated by the N-terminal end of PTH and causes intracellular activation through a G-protein coupled mechanism. 1 The main stimulus for PTH secretion is low plasma calcium (Ca 2+ ) levels. The concentration of Ca 2+ is tightly regulated by complex feedback mechanisms where the calcium-sensing receptor (CaSR) is a main regulator. The sensitivity of the CaSR can graphically be explained by a sigmoidal curve, where small changes in Ca 2+ can lead to significant changes in the subsequent PTH secretion. As a result of low Ca 2+ , PTH is secreted by the parathyroid cells. The PTH stimulation acts on kidney cells by increasing renal tubular reabsorption of calcium 2 and the conversion of 25-hydroxy vitamin D (25OHD) to 1,25-dihydroxy vitamin D (1,25(OH) 2 D) by activation of the renal 1a-hydroxylase. 3 Secondary, 1,25(OH) 2 D increases the calcium absorption from the intestine. In the bone, PTH controls Ca 2+ release to the extracellular fluid 4 with both a rapid release from a calcium pool as a buffer mechanism and the more slow mechanism with stimulation of increased bone turnover. 4 The effect is an increase in plasma Ca 2+ . Also plasma phosphate is regulated by PTH but in the opposite direction. Hence, an increased plasma PTH leads to increased renal phosphate excretion 5 with decreased plasma phosphate levels. © TO U CH MEDICAL MED IA 2013 PTH is a major regulator of bone remodeling, the process by which the skeleton is being renewed constantly throughout life (see Figure 1). The primer of bone remodeling is bone resorption by osteoclasts, which after a reversal phase changes to bone formation by osteoblasts. 6 This process of bone remodeling is critical to maintain healthy bone. The regulation of the remodeling process goes primarily through the osteoblasts, which expresses receptors for both PTH and 1,25(OH) 2 D. 7 It is believed that PTH mainly has an indirect stimulation on osteoclasts by binding to neighboring osteoblasts. 8 Elevated PTH levels induce an increased release of receptor activator of nuclear factor-kb ligand (RANKL), which binds to its receptor (RANK) on osteoclast precursor cells leading to activation and formation of osteoclasts. 9 In younger and otherwise healthy individuals, increased activation of osteoclasts is normally followed by a balanced formation of new bone under the process of bone remodeling 10 (see Figure 2). However, this increased resorption of bone is seen in both trabecular and cortical bone in PHPT and causes a temporary, but reversible, bone loss if the remodeling cavities are refilled with new bone. The PTH-induced increase in bone turnover is probably the main reason for reduced bone mineral density (BMD) in PHPT. However, if the remodeling process is not balanced, the increased bone resorption will lead to a catabolic state with a subsequent loss of bone. This mechanism may also explain part of the reduced BMD in PHPT. The distribution of balanced and unbalanced bone remodeling is not known. 181