Author details

Ross A. Hauser<sup>1</sup> and Barbara A. Woldin<sup>2</sup> \*


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**Chapter 6**

**Provisional chapter**

**Skeletal Manifestations of Hyperparathyroidism**

**Skeletal Manifestations of Hyperparathyroidism**

DOI: 10.5772/intechopen.74034

The presentation of hyperparathyroidism changed over the last decades which gave rise to more variable presentations than before. Hyperparathyroidism has a catabolic effect on the skeleton whether the disease is symptomatic or asymptomatic or normocalcemic. It is now understood that the effect of parathyroid hormone (PTH) on the bone is mediated by complex interaction between different bone cells and cells of the immune system especially T lymphocytes. Protecting the skeletal system against bone loss and pathological fractures is among the important treatment goals of hyperparathyroidism. To achieve this goal, more complex laboratory tests to monitor the bone turnover and imaging techniques and modalities as high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) are employed. These imaging techniques showed the affection of microarchitecture of the cortical and the trabecular bone. For the time being, surgery and alendronate treatment are believed to reverse the catabolic effect of hyperparathyroidism on the bone. Vitamin D supplementation in case of vitamin D

**Keywords:** osteitis fibrosa cystica (OFC), bisphosphonates, brown tumor, RANKL,

Over the last hundred years, the effect of parathyroid hormone (PTH) on bone metabolism was extensively discussed. PTH acts on the bone cells through several mediators, and its action involves a variety of cells. It is now understood that parathyroid hormone has both catabolic and anabolic effects on bone metabolism [1]. Mandl in Austria was the first to prove that the enlarged parathyroid was responsible for the skeletal manifestations of hyperparathyroidism after the first successful removal of parathyroid adenoma [2]. The clinical picture of the disease also changed dramatically over the years from a disease of "stones, bones,

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

deficiency may also has a protective effect on the skeleton.

parathyroid hormone, bone metabolism

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74034

Ahmed Khedr

**Abstract**

**1. Introduction**

Ahmed Khedr

## **Skeletal Manifestations of Hyperparathyroidism Skeletal Manifestations of Hyperparathyroidism**

DOI: 10.5772/intechopen.74034

#### Ahmed Khedr Ahmed Khedr

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74034

#### **Abstract**

The presentation of hyperparathyroidism changed over the last decades which gave rise to more variable presentations than before. Hyperparathyroidism has a catabolic effect on the skeleton whether the disease is symptomatic or asymptomatic or normocalcemic. It is now understood that the effect of parathyroid hormone (PTH) on the bone is mediated by complex interaction between different bone cells and cells of the immune system especially T lymphocytes. Protecting the skeletal system against bone loss and pathological fractures is among the important treatment goals of hyperparathyroidism. To achieve this goal, more complex laboratory tests to monitor the bone turnover and imaging techniques and modalities as high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) are employed. These imaging techniques showed the affection of microarchitecture of the cortical and the trabecular bone. For the time being, surgery and alendronate treatment are believed to reverse the catabolic effect of hyperparathyroidism on the bone. Vitamin D supplementation in case of vitamin D deficiency may also has a protective effect on the skeleton.

**Keywords:** osteitis fibrosa cystica (OFC), bisphosphonates, brown tumor, RANKL, parathyroid hormone, bone metabolism

#### **1. Introduction**

Over the last hundred years, the effect of parathyroid hormone (PTH) on bone metabolism was extensively discussed. PTH acts on the bone cells through several mediators, and its action involves a variety of cells. It is now understood that parathyroid hormone has both catabolic and anabolic effects on bone metabolism [1]. Mandl in Austria was the first to prove that the enlarged parathyroid was responsible for the skeletal manifestations of hyperparathyroidism after the first successful removal of parathyroid adenoma [2]. The clinical picture of the disease also changed dramatically over the years from a disease of "stones, bones,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

abdominal groans, thrones and psychiatric overtone" to a disease which can be only detected by elevated calcium and the PTH level on laboratory tests or even the elevated PTH level with no hypercalcemia [2, 3]. This change in clinical presentation was accompanied by the introduction of newer lab tests to assess bone turnover and newer imaging techniques to assess the bone quality [2]. The treatment modalities also evolved, allowing more individualized approach for treating each patient [4].

There was less RANKL expression and less osteoclast number in the group of mice lacking RANKL [25]. Another study was designed with a co-culture of osteoclast precursors and osteocytes. The study showed that RANKL is provided through dendritic processes of osteocytes to osteoclast precursor and that soluble RANKL had less contribution to osteoclastogenesis [27]. In humans, the RANKL/osteoprotegerin (OPG) ratio is higher in patients with PHPT than controls. This ratio is decreased with parathyroidectomy (PTx) or medical treatment by alendronate [28]. Another study on patients with PHPT showed that RANKL correlated with bone resorption markers in these patients and suggested that it can be used to determine patients of PHPT with greater risk of bone loss [13]. Another study was conducted on patients with PHPT where transiliac bone biopsy was done before PTx and 12 months after surgery and mRNA for RANKL and OPG were measured. The study showed that the mRNA ratio of RANKL/OPG

Skeletal Manifestations of Hyperparathyroidism http://dx.doi.org/10.5772/intechopen.74034 89

PTH increases RANKL/OPG ratio with continuous exposure to high dose which produces catabolic effect as in hyperparathyroidism. This results in increased bone turnover, osteopenia, and bone loss in hyperparathyroidism. In addition, several extraskeletal manifestations of hyperparathyroidism are due to increased bone catabolism and hypercalcemia as nephrolithiasis, renal failure, peptic ulcer, and mental changes [2]. On the other hand, intermittent low-dose exposure to PTH has an anabolic effect through the SOST/sclerostin pathway [6]. The OPG-RANK-RANKL pathway is the mechanism by which hyperparathyroidism induces bone catabolism. PTH regulates the production of RANKL and its soluble decoy receptor OPG by osteoblasts and osteocytes [29–31]. RANKL binds to the receptor activator of nuclear factor kappa-B (RANK) on the osteoclast precursor stimulating their differentiation to osteoclasts and on the surface of the osteoclasts increasing their bone-resorbing activity. OPG inhibits the action of RANKL by binding to RANKL, thus preventing its access to the receptor RANK. In this way, the process of bone resorption is controlled by the balance between the concentration of RANKL and OPG [32–36]. In rats, continuous infusion of human PTH increased RANKL and RANKL mRNA expression and decreased OPG and OPG mRNA [37]. In vitro studies also showed that PTH activates of cAMP/PKA–CREB pathway increase the Tnfsf11 gene encoding RANKL, whereas a PTH inhibits the mRNA encoding for OPG expres-

decreased significantly after surgery [13].

sion through a PKA-CREB-AP-1 pathway [38–40].

**immune system**

**2.2. Effect of parathyroid hormone on cells of the bone marrow and cells of the** 

Cells of bone marrow also play a role in the effect of PTH on bone metabolism. Lymphocytes are believed to play a role on bone metabolism. T lymphocytes express PPR [23]. T cells express RANKL and CD40L on their surface that binds with RANK and CD40 in osteoclast precursors and osteoclasts to stimulate them [13, 41, 42]. Th17 cells form a subset of T lymphocytes that contribute to bone resorption. TH17 cells secrete IL-17, RANKL, TNF-α, IL-1, and IL-6, along with low levels of IFN-γ which contribute to osteoclastogenesis [43–46]. IL-17 stimulates the secretion of RANKL by osteoblasts and osteocytes and upregulates RANK [46, 47]. This is consistent with a human study that showed statistically significant elevation of IL-17 in postmenopausal women who had osteoporosis when compared with postmenopausal women who had osteopenia [47]. It is also noted that cPTH stimulates the production of TGF-β, IL-6, and TNF-α by bone cells and
