**4. Skeletal abnormalities in asymptomatic primary hyperparathyroidism**

#### **4.1. Manifestations**

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

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

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].
