**3. Skeletal abnormalities in symptomatic hyperparathyroidism**

### **3.1. Incidence**

Hyperparathyroidism was first described in 1891 by von Recklinghausen. Despite of the fact that primary hyperparathyroidism was classically described as disease of "stones, bones, abdominal groans, thrones, and psychiatric overtone," the presentation of the disease changed dramatically over the past decades. Nowadays, the classical presentation with osteitis fibrosa cystica and pathological fractures is rarely seen in developed countries. Currently, larger numbers of patients are being identified with neuropsychiatric or cardiac manifestation and laboratory studies in the USA and Europe [2, 56]. In developing countries, the symptomatic form of PHPT was prevalent for a long time, but some countries as Brazil and China are having a shift toward the asymptomatic disease. However, other countries as India, Iran, Saudi Arabia, and Thailand still have high prevalence of the symptomatic form of the disease with pronounced skeletal manifestations [56–58].

#### **3.2. Clinical manifestations**

The signs and symptoms of severe bone disease include bone pain and pathologic fractures. Skeletal muscles are also affected by hyperparathyroidism where the patients have proximal muscle weakness and hyperreflexia [2, 59].

One of the features of skeletal involvement in hyperparathyroidism is hungry bone syndrome. It is characterized by hypocalcemia and hypophosphatemia following PTx. It is thought to be due to withdrawal of osteoclast stimulation by high levels of PTH. This condition is treated by high doses of calcium and vitamin D [60, 61].

#### **3.3. Investigations**

#### *3.3.1. Imaging*

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

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].

**3. Skeletal abnormalities in symptomatic hyperparathyroidism**

Hyperparathyroidism was first described in 1891 by von Recklinghausen. Despite of the fact that primary hyperparathyroidism was classically described as disease of "stones, bones, abdominal groans, thrones, and psychiatric overtone," the presentation of the disease changed dramatically over the past decades. Nowadays, the classical presentation with osteitis fibrosa cystica and pathological fractures is rarely seen in developed countries. Currently, larger numbers of patients are being identified with neuropsychiatric or cardiac manifestation and laboratory studies in the USA and Europe [2, 56]. In developing countries, the symptomatic form of PHPT was prevalent for a long time, but some countries as Brazil and China are having a shift toward the asymptomatic disease. However, other countries as India, Iran, Saudi Arabia, and Thailand still have high prevalence of the symptomatic form of the disease with pronounced skeletal manifestations [56–58].

The signs and symptoms of severe bone disease include bone pain and pathologic fractures. Skeletal muscles are also affected by hyperparathyroidism where the patients have proximal

One of the features of skeletal involvement in hyperparathyroidism is hungry bone syndrome. It is characterized by hypocalcemia and hypophosphatemia following PTx. It is thought to be

the OPG secretion, thus increasing the RANKL/OPG ratio [7].

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

**3.1. Incidence**

**3.2. Clinical manifestations**

muscle weakness and hyperreflexia [2, 59].

#### *3.3.1.1. Radiography*

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 lesions are nonneoplastic [2].

#### *3.3.1.2. Bone mineral density*

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 effect on cortical bone [2, 56].

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

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 trabeculae and thinner cortices [62–64].

#### *3.3.1.4. Trabecular bone score (TBS)*

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 strength [65–67].

#### *3.3.2. Histomorphometry*

Histomorphometry of transiliac biopsy will show reduced width of the cortex with increased porosity, while the trabecular bone is preserved [14].

#### *3.3.3. Laboratory tests*

In severe PHPT, serum calcium and parathormone are elevated. There are special markers for bone elevation as osteocalcin, type I procollagen peptide, and alkaline phosphatase. Alkaline phosphatase is much above the normal in all cases of hyperparathyroidism with increased bone turnover. Markers of bone resorption are also typically elevated PHPT. These include deoxypyridinoline, N-telopeptide, and C-telopeptide. These markers are products of breakdown of type 1 collagen [2]. Renal functions and urinary calcium should be evaluated. 25OH vitamin D levels should be as lower as the levels of 25OH vitamin D correlate with higher bone turnover and lower BMD, and both improve with repletion of 25OH vitamin D [68, 69].

**4.2. Natural history of bone disease in asymptomatic hyperparathyroidism**

**5. Skeletal abnormalities in normocalcemic primary** 

**hyperparathyroidism**

**5.1. Manifestations**

Age and female genders are associated with higher fracture risk in PHPT [73]. Currently, it is still unclear whether fracture risk assessment tools as FRAX can help to predict risk of fractures in patients with PHPT or not [14]. Concerning changes in BMD over time, Rao et al. monitored 80 patients with asymptomatic PHPT for a mean of 46 month. They did not observe deterioration of biochemical markers nor BMD measurements [74]. Silverberg et al. followed up 121 patients with PHPT of whom 101 were asymptomatic for up to 10 years. Twenty-five percent of patients showed disease progression. They also noted that patients younger than 50 years old had more likelihood of disease progression [71]. Rao et al. conducted randomized controlled trial on patients with PHPT and concluded that BMD at the hip and spine improves after PTx [76]. Rubin et al. studied 116 patients with PHPT of whom 99 were asymptomatic, PTX improved the biochemical markers and BMD, and without surgery PHPT progressed in one third of the cases [76]. Eller-Vainicher et al. studied 92 patients with PHPT and 98 controls for 24 months. DEXA scan and TBS in patients treated surgically and conservatively. In the surgical group, BMD and TBS increased significantly although it remained lower than controls. In the conservative group, BMD showed a decrease which was not statistically significant, and TBS showed a decrease which was not statistically significant; except in three patients who had vertebral fractures, the TBS showed a statistically significant decrease [75]. Hansen et al. measured BMD and HR-pQCT in women with PHPT before and 1 year after PTx. BMD improved after PTx, and HR-pQCT showed improvement of the cortical and trabecular parameters of the radius and tibia [77].

Skeletal Manifestations of Hyperparathyroidism http://dx.doi.org/10.5772/intechopen.74034 93

This is a cohort of patients which includes patients with normal total and ionized calcium but elevated PTH in the absence of causes of secondary hyperparathyroidism. This may be due to target organ resistance of the bone and kidney, or these patients are in early stages of the disease [78, 79]. Lowe et al. described a cohort of patients in whom 57% had osteoporosis, 11% had fragility fractures, and 14% had renal stones [80]. Amaral et al. compared normocalcemic to hypercalcemic PHPT patients. They found that 15% of normocalcemic patients had previous fractures compared to 10.8% of normocalcemic patients and the incidence of renal stones was 18.2 in normocalcemic vs. 18.9% of hypercalcemic patients [80]. Charopoulos et al. used peripheral quantitative CT to compare the effect of normocalcemic PHPT to the effect of hypercalcemic PHPT on volumetric BMD and bone geometry. They noted the catabolic effect on both groups although it is more severe in the hypercalcemic group. In the normocalcemic group, cortical properties were adversely affected, while the trabecular properties were preserved [80].

The natural history of bone loss in normocalcemic hyperparathyroidism is not fully defined. Lowe et al. showed decrease in BMD by at least 5% in 43% of the patients [80]. Koumakis

**5.2. Natural history of bone disease in asymptomatic hyperparathyroidism**
