**6. Treatment**

#### **6.1. Effect of surgery on the skeletal manifestations of hyperparathyroidism**

Skeletal affection is among the indications of surgery in hyperparathyroidism. Even in asymptomatic cases, surgery is suggested for perimenopausal or postmenopausal women and men 50 years or older who have a T-score of −2.5 or less for any skeletal site. In premenopausal women and men under 50 years old, T-score of less than −2.5 is the cutoff for surgery. The presence of fragility fractures is also among the surgical indication [2, 4, 81].

Surgery improves the bone turnover marker and PTH level. Within the first year following surgery, the BMD improves [70, 71, 82, 83]. This is due to uncoupling of bone resorption where the osteoclast stimulation by PTH stops, while bone formation continues [84]. Rubin et al. showed that the gain in BMD was sustainable up to 15 years following surgery at cortical and cancellous sites despite of expected age-related losses in BMD. The increases in BMD were recorded in the study at years 1, 5, and 10 and showed that the lumbar spine increased to 9, 6, and 12%; the femoral neck 1, 7, and 10%; and the distal radius 4, 8, and 7% [70]. Christiansen et al. studied the BMD and bone turnover markers for the first 6 months after surgery. They reported that the bone turnover markers were normalized and increased bone density in regions rich in cancellous bone but not cortical bone [82]. Similarly, Silverberg et al. noted improvement of BMD in lumbar spine and femoral neck but not the radius [71]. This may be explained by the fact that remodeling in cortical sites is slower than in trabecular bone. Thus, it takes a longer time for changes to be more pronounced [70]. Surgery also decreases the risk of fractures in hyperparathyroidism [72, 85, 86]. Vestergaard et al. demonstrated that the risk of fractures started to increase 10 years prior to surgery and reached its maximum 5–6 years following surgery. This risk falls back to normal after surgery [72]. Rudser et al. compared patients on dialysis who receive PTx to patients on dialysis without PTx. Fracture risks were lower among hemodialysis patients who underwent PTx compared to the dialysis patients who did not undergo PTx [84].

#### **6.2. Effect of pharmacological treatment on skeletal manifestations of hyperparathyroidism**

#### *6.2.1. Bisphosphonates*

Bisphosphonates (BP) are used in treatment of hyperparathyroidism as they act by inhibiting osteoclastic activity which is the cause of hypercalcemia and bone loss [2]. Several studies assessed the use of alendronate in hyperparathyroidism. Studies reported a reduction in the level of bone turnover markers and an increase in BMD. The increase in BMD was more for the trabecular than the cortical sites [87–92]. Although alendronate can lower the serum calcium initially, serum calcium tends to rise over 6 months, and the level of PTH may increase more than the pretreatment level [2, 90–93]. Pamidronate in several studies showed lowering of the serum calcium. However, due to limited time frame, no changes in BMD nor complications 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].

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 lived.

#### *6.2.2. Cinacalcet*

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

Skeletal affection is among the indications of surgery in hyperparathyroidism. Even in asymptomatic cases, surgery is suggested for perimenopausal or postmenopausal women and men 50 years or older who have a T-score of −2.5 or less for any skeletal site. In premenopausal women and men under 50 years old, T-score of less than −2.5 is the cutoff for surgery. The

Surgery improves the bone turnover marker and PTH level. Within the first year following surgery, the BMD improves [70, 71, 82, 83]. This is due to uncoupling of bone resorption where the osteoclast stimulation by PTH stops, while bone formation continues [84]. Rubin et al. showed that the gain in BMD was sustainable up to 15 years following surgery at cortical and cancellous sites despite of expected age-related losses in BMD. The increases in BMD were recorded in the study at years 1, 5, and 10 and showed that the lumbar spine increased to 9, 6, and 12%; the femoral neck 1, 7, and 10%; and the distal radius 4, 8, and 7% [70]. Christiansen et al. studied the BMD and bone turnover markers for the first 6 months after surgery. They reported that the bone turnover markers were normalized and increased bone density in regions rich in cancellous bone but not cortical bone [82]. Similarly, Silverberg et al. noted improvement of BMD in lumbar spine and femoral neck but not the radius [71]. This may be explained by the fact that remodeling in cortical sites is slower than in trabecular bone. Thus, it takes a longer time for changes to be more pronounced [70]. Surgery also decreases the risk of fractures in hyperparathyroidism [72, 85, 86]. Vestergaard et al. demonstrated that the risk of fractures started to increase 10 years prior to surgery and reached its maximum 5–6 years following surgery. This risk falls back to normal after surgery [72]. Rudser et al. compared patients on dialysis who receive PTx to patients on dialysis without PTx. Fracture risks were lower among hemodialysis patients who underwent PTx compared to the dialysis patients who did not undergo PTx [84].

**6.1. Effect of surgery on the skeletal manifestations of hyperparathyroidism**

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

presence of fragility fractures is also among the surgical indication [2, 4, 81].

**6.2. Effect of pharmacological treatment on skeletal manifestations of** 

Bisphosphonates (BP) are used in treatment of hyperparathyroidism as they act by inhibiting osteoclastic activity which is the cause of hypercalcemia and bone loss [2]. Several studies assessed the use of alendronate in hyperparathyroidism. Studies reported a reduction in the level of bone turnover markers and an increase in BMD. The increase in BMD was more for the trabecular than the cortical sites [87–92]. Although alendronate can lower the serum calcium initially, serum calcium tends to rise over 6 months, and the level of PTH may increase more than the pretreatment level [2, 90–93]. Pamidronate in several studies showed lowering of the serum calcium. However, due to limited time frame, no changes in BMD nor complications

the postoperative measurement [14].

**6. Treatment**

**hyperparathyroidism**

*6.2.1. Bisphosphonates*

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].

#### *6.2.3. Vitamin D and calcium*

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].

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

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

Denosumab is a monoclonal antibody against RANKL that inhibits the binding of RANKL to RANK [125]. A study was conducted on patients with secondary hyperparathyroidism on dialysis in whom denosumab was administered. The BMD improved in the femoral neck and lumbar spine. However, a transient increase in PTH levels occurred in the patients.

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