**5. Skeletal abnormalities in normocalcemic primary hyperparathyroidism**

#### **5.1. Manifestations**

*3.3.3. Laboratory tests*

**hyperparathyroidism**

**4.1. Manifestations**

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].

In 1970s, the wide availability of measurement of serum calcium changed the clinical presentation of hyperparathyroidism giving rise to the entity of asymptomatic primary hyperparathyroidism [14]. These are patients with hypercalcemia and elevated PTH but who are discovered accidentally while doing laboratory studies [58]. These patients have no X-ray finding of symptomatic hyperparathyroidism previously described [58]. These patients show decreased bone mass in cortical sites when measured by DEXA scan. Thus, DEXA scan shows reduction of bone mineral density at distal 1/3 of forearm (which is composed primarily of cortical bone), while bone density of lumbar spine (which is formed mainly of trabecular bone) is preserved. However, bone scan may remain stable for years in patients with asymptomatic hyperparathyroidism. Rubin et al. noted that the BMD of the lumbar spine remained stable for 15 years while it started to fall in cortical sites before 10 years [70, 71]. Micro-CT and histomorphometric studies show reduction of cortical bone with preservation of cancellous bone in PHPT [70, 71]. However, clinical studies showed that patients with hyperparathyroidism have higher risk of fractures both at cortical and cancellous sites [72, 73]. HR-pQCT helped to resolve this controversy. 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]. These studies also highlighted that weight bearing is a factor that can prevent the microarchitectural deterioration where they showed that the radius is more negatively affected than the tibias [63, 64]. Stein et al. performed individual trabecula segmentation that gave an insight into the trabecular microstructure. They found that the number of plate-like trabeculae is reduced relative to the rod-like trabeculae (decrease P-R ratio); there is reduced connectivity and less axially aligned trabecular network [64]. Another imaging modality which can show skeletal affection in asymptomatic cases is the trabecular bone score (TBS). Romagnoli et al. showed that TBS was significantly lower in patients with PHPT compared to controls. Among patients with PHPT, TBS was significantly lower in patients with vertebral fractures when compared to patients without vertebral fractures [74]. Eller-Vainicher et al. showed that TBS was associated

**4. Skeletal abnormalities in asymptomatic primary** 

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

with vertebral fractures regardless of age, gender, BMD, and BMI [75].

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].

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

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 et al. measured BMD before and 12 months after PTx for patients with normocalcemic and hypercalcemic PHPT. Both groups showed statistically significant improvement of BMD at the postoperative measurement [14].

were reported [94–100]. Clodronate use was associated with lowering of the serum calcium [101–103]. Several studies using clodronate reported lowering of urinary hydroxyproline and hence decreased bone turnover [101–103]. The use of risedronate in treatment of hyperparathyroidism was assessed in few studies [104, 105]. Tournis et al. reported that surgery is superior to risedronate as it improved the BMD and trabecular mineralization. Risedronate treatment in their study did not result in significant change in volumetric BMD or peripheral quantitative computed tomography [104]. A small number of studies reported the use of several BPs. Lee et al. reported the can prevent hungry bone syndrome among a very small number of patients [104]. Two other studies reported increase in BMD in the lumbar spine and hip [85, 106].

Skeletal Manifestations of Hyperparathyroidism http://dx.doi.org/10.5772/intechopen.74034 95

In conclusion, alendronate is the most studied BP in hyperparathyroidism. It decreases bone turnover and increased BMD. The effect of alendronate on serum calcium appears to be short

This is a calcimimetic agent which increases the sensitivity of calcium-sensing receptors of the parathyroid gland to calcium, thus decreasing PTH secretion [107]. The effect of cinacalcet on bone turnover markers and BMD appears to be controversial. Several studies measured bone turnover markers with either decrease in the markers [108], no change [109, 110], or increase in the level of the markers [111, 112]. Similarly, the reported effects on BMD were an increase in BMD [113], a decrease [114], and no change [108, 111, 112]. Faggiano et al. compared cinacalcet monotherapy with cinacalcet with alendronate. The patients who received the combined therapy had better improvement of BMD in lumbar spine and hip compared to the monotherapy group. There was no significant difference between biochemical changes in both groups [108]. Moe et al. studied the effect of cinacalcet in reducing the fracture risk in patients receiving hemodialysis. There was no significant effect of cinacalcet on fracture reduction in the intentionto-treat analysis. However, a lag-sensoring analysis which took into consideration the crossover effect showed significant reduction of fracture risk in patients who received cinacalcet [84].

Dietary calcium deficiency can induce elevation of PTH levels. Low vitamin D levels are associated with increased bone turnover, deteriorated hip geometry, and lower BMD [68, 84, 115]. Patients with low calcium intake and PHPT who received calcium supplementation had lower levels of PTH and improved BMD of femoral neck [116]. For patients with vitamin D deficiency, vitamin D repletion may decrease PTH levels and improved bone mineral density [116–118]. However, vitamin D supplementation may slightly increase serum calcium levels and urinary calcium excretion; thus, monitoring of calcium levels is valuable [81, 119, 120].

Estrogen was found to improve BMD in women with hyperparathyroidism. The BMD of the lumbar spine and femoral neck increases, and bone turnover markers decrease with estrogen administration which has no or minimal effect on serum calcium [121, 122]. Raloxifene was also associated with improved BMD in PHPT [123, 124]. However, there is no data on the

*6.2.4. Other treatments of hyperparathyroidism which affect bone metabolism*

effect of estrogen or raloxifene on reducing the risk of fracture [120].

lived.

*6.2.2. Cinacalcet*

*6.2.3. Vitamin D and calcium*
