**2. Action of parathyroid hormone on the bone in hyperparathyroidism**

The main function of PTH is to maintain calcium levels within the normal range thorough its action on the bone, kidneys, and intestine. It also decreases serum phosphorous through inhibiting renal reabsorption [5, 6]. PTH can produce catabolic or anabolic effect on bone metabolism depending on the level of the hormone, periodicity, and duration of exposure [6, 7]. Primary hyperparathyroidism (PHPT), continuous PTH infusion (cPTH), and intermittent PTH treatment (iPTH) increase bone turnover in trabecular and cortical bone and elevate the markers for bone resorption and formation [2, 8–10]. PHPT and cPTH enhance cortical bone loss by increasing osteoclastic activity but produce cancellous bone that is relatively preserved or modestly increased [2, 9, 11]. iPTH treatment stimulates trabecular bone formation by osteoblast stimulation and can cause small cortical bone loss [12, 13]. The pattern of bone loss in PHPT is different from the pattern of bone loss in osteoporosis. In osteoporosis, the trabecular bone loss predominates, while in PHPT the cortical bone loss predominates [14].

#### **2.1. Action of parathyroid hormone on bone cells**

Normally, bone structural integrity is maintained by the process or remodeling where the bone is removed by osteoclasts and new bone is synthesized by osteoblasts [15]. The osteoclasts and osteoblasts are arranged in a structure called the basic multicellular unit (BMU). A BMU consists of osteoclasts in front with osteoblasts, some blood vessels, and connective tissue behind [16, 17]. Osteoclasts are formed by fusion of mononuclear precursors, while osteoblasts originate from undifferentiated mesenchymal cells [16, 18]. Parathyroid hormone produces its effects by binding to its receptor PPR (also known as PTH-1R). While osteoblasts, osteocytes, and lymphocytes, mesenchymal stromal cells express PPR, osteoclasts respond indirectly to PTH through various mediators and cytokines produced by cells which carry PPR [6, 19–23]. It is now believed that osteocytes are the primary cellular target of PTH in the bone. Osteocytes are the main cells that express PPR in the musculoskeletal system [14]. Saini et al. designed a study where they generated mice with PPR deletion in osteocytes. These mice showed significant increase in bone mineral density (BMD), reduced osteoblast activity, and decreased skeletal response to anabolic or catabolic PTH regimen [24]. Other studies also supported the fact that osteocytes rather than osteoblasts are the main source of the receptor activator of nuclear factor kappa-B ligand (RANKL) in the process of osteoclastogenesis [25, 26]. Where mice lacking RANKL in osteocytes had less bone loss compared to control mice when they are exposed to dietary calcium deficiency for 30 days causing secondary hyperparathyroidism. 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 decreased significantly after surgery [13].

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

The main function of PTH is to maintain calcium levels within the normal range thorough its action on the bone, kidneys, and intestine. It also decreases serum phosphorous through inhibiting renal reabsorption [5, 6]. PTH can produce catabolic or anabolic effect on bone metabolism depending on the level of the hormone, periodicity, and duration of exposure [6, 7]. Primary hyperparathyroidism (PHPT), continuous PTH infusion (cPTH), and intermittent PTH treatment (iPTH) increase bone turnover in trabecular and cortical bone and elevate the markers for bone resorption and formation [2, 8–10]. PHPT and cPTH enhance cortical bone loss by increasing osteoclastic activity but produce cancellous bone that is relatively preserved or modestly increased [2, 9, 11]. iPTH treatment stimulates trabecular bone formation by osteoblast stimulation and can cause small cortical bone loss [12, 13]. The pattern of bone loss in PHPT is different from the pattern of bone loss in osteoporosis. In osteoporosis, the trabecular bone loss predominates, while in PHPT the cortical bone loss predominates [14].

Normally, bone structural integrity is maintained by the process or remodeling where the bone is removed by osteoclasts and new bone is synthesized by osteoblasts [15]. The osteoclasts and osteoblasts are arranged in a structure called the basic multicellular unit (BMU). A BMU consists of osteoclasts in front with osteoblasts, some blood vessels, and connective tissue behind [16, 17]. Osteoclasts are formed by fusion of mononuclear precursors, while osteoblasts originate from undifferentiated mesenchymal cells [16, 18]. Parathyroid hormone produces its effects by binding to its receptor PPR (also known as PTH-1R). While osteoblasts, osteocytes, and lymphocytes, mesenchymal stromal cells express PPR, osteoclasts respond indirectly to PTH through various mediators and cytokines produced by cells which carry PPR [6, 19–23]. It is now believed that osteocytes are the primary cellular target of PTH in the bone. Osteocytes are the main cells that express PPR in the musculoskeletal system [14]. Saini et al. designed a study where they generated mice with PPR deletion in osteocytes. These mice showed significant increase in bone mineral density (BMD), reduced osteoblast activity, and decreased skeletal response to anabolic or catabolic PTH regimen [24]. Other studies also supported the fact that osteocytes rather than osteoblasts are the main source of the receptor activator of nuclear factor kappa-B ligand (RANKL) in the process of osteoclastogenesis [25, 26]. Where mice lacking RANKL in osteocytes had less bone loss compared to control mice when they are exposed to dietary calcium deficiency for 30 days causing secondary hyperparathyroidism.

approach for treating each patient [4].

**hyperparathyroidism**

**2. Action of parathyroid hormone on the bone in** 

88 Anatomy, Posture, Prevalence, Pain, Treatment and Interventions of Musculoskeletal Disorders

**2.1. Action of parathyroid hormone on bone cells**

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

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

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 stromal cells [7, 48, 49]. TGF-β and IL-6 direct the differentiation of naive CD4+ cells into TH17 cells [50–52]. TNF-α plays also an important role as a mediator of PTH catabolic action. PTH stimulates T cells to produce TNF-α. In mice lacking T-cell TNF-α, PTH failed to produce bone resorption but did not affect bone formation. Thus, in these mice there was no cortical bone loss, and there was increased trabecular bone formation [19]. TNF-α stimulates osteoclast formation and activity by multiple mechanisms. TNF-α increases the production of RANKL by osteoblasts and osteocytes. It also increases the expression of CD40 by stromal cells and osteoblasts increasing their responsiveness to CD40L expressed by T cells. Activation of CD40 on stromal cells and osteoblasts decreases the OPG secretion, thus increasing the RANKL/OPG ratio [7].

due to withdrawal of osteoclast stimulation by high levels of PTH. This condition is treated

Skeletal Manifestations of Hyperparathyroidism http://dx.doi.org/10.5772/intechopen.74034 91

Plain X-rays can show the classical findings of osteitis fibrosa cystica. This is characterized by marked thinning of the cortex (demineralization). Salt and pepper appearance for skull X-rays is also seen. Bone resorption of distal third of the clavicle is also seen. Hand X-rays show subperiosteal bone erosions in the distal phalanges and the lateral aspects of middle phalanges. Lytic lesions can also be seen in the pelvis and long bones with pathological fractures. Lytic lesions are referred to as brown tumors; these are a mixture of hemosiderin (hence, the brown color on pathological examination), woven bone, fibrous tissue, and osteoclasts. However, the

Bone mineral density can be measured by dual energy X-ray absorptiometry (DEXA) scan in all patients where measurements should be taken for lumbar spine, hip regions (total hip and femoral neck), and distal 1/3 of the radius. It is important to measure the bone mineral density in distal radius as it is a cortical site, and hyperparathyroidism is known to have catabolic

This is a noninvasive technique that allows assessment of the cortical and trabecular bone quality in PHPT [56]. HR-pQCT measures volumetric bone density, bone geometry, skeletal microarchitecture, and bone strength in the cortical and trabecular compartments. HR-pQCT showed that microarchitectural deterioration in both cortical and cancellous sites has decreased volumetric densities, more widely spaced, and heterogeneously distributed

TBS is obtained from DEXA scan by applying special software. It is a textural analysis that provides an indirect index of trabecular microarchitecture. It can differentiate between DEXA scans showing similar bone densities. A high TBS is associated with a dense trabecular network and greater bone strength, and a low TBS indicates poor microarchitecture and poor

Histomorphometry of transiliac biopsy will show reduced width of the cortex with increased

*3.3.1.3. High-resolution peripheral quantitative computed tomography (HR-pQCT)*

by high doses of calcium and vitamin D [60, 61].

**3.3. Investigations**

*3.3.1.1. Radiography*

lesions are nonneoplastic [2].

*3.3.1.2. Bone mineral density*

effect on cortical bone [2, 56].

trabeculae and thinner cortices [62–64].

porosity, while the trabecular bone is preserved [14].

*3.3.1.4. Trabecular bone score (TBS)*

strength [65–67].

*3.3.2. Histomorphometry*

*3.3.1. Imaging*

Bone marrow macrophages also play a role in the action of PTH on the bone. Macrophages express PPR. Depletion of the precursors of macrophages decreases the anabolic effect of iPTH [19]. The monocyte chemoattractant protein-1 (MCP-1) which is a chemotactic factor for monocyte and macrophages is a mediator for PHT-induced bone resorption [6]. MCP-1 was proven to attract pre-osteoclast in in vitro studies, thus increasing bone resorption [53]. It was found that the expression for MCP-1 increased by cPTH and iPTH in rat osteoblastic cells. With cPTH the MCP-1 expression was sustained, while with the anabolic protocol, the expression of MCP-1 was transient yet more pronounced. This suggests that the transient increase of bone resorption may be necessary before the anabolic effect of PTH on the bone [53, 54]. In human studies, MCP-1 levels correlate with PTH levels in patients with PHPT. After PTx, the levels of MCP-1 decreased significantly starting from 15 minutes following parathyroid adenoma removal [55].
