New diagnostic and therapeutic aspects of subclinical forms of parathyroid gland diseases

1. RESEARCH QUESTION Can alendronate and vitamin D improve the bone mineral density in patients with normocalcemic primary hyperparathyroidism? ABSTRACT Introduction: normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. Methods and design: the study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. Results: after 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group (p = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months (p <0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. Conclusion: the results of this study indicate that alendronate/cholecalciferol may increase BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium. 2. RESEARCH QUESTION What is the prevalence and the metabolic bone profile of the normocalcaemic hypoparathyroidism? ABSTRACT Introduction: there are no consistent data on the prevalence and bone status of normocalcaemic hypoparathyroidism (NHYPO) as defined by normal adjusted calcium and low PTH level. Our aim was to determine the prevalence and the metabolic bone profile of NHYPO in older women, assessing its evolution over time. The second objective was to evaluate the prevalence of other calcium metabolic disorders. Methods and design: the Osteoporosis and Ultrasound Study (OPUS) is a 6-yr prospective study of fracture-related factors. A total of 2419 older women (age 55-79 yrs) and 258 younger women (age 30-40 yrs) participated. Complete follow-up data were available in 1416 subjects. After calculating the adjusted calcium according to James' formula, we identified 'abnormal' calcium and PTH using Mahalanobis distances and allocated older women into different pathological categories using reference intervals from the healthy young women. Results: we identified 57 subjects with NHYPO (2.4%). These women had lower than expected bone turnover as assessed by bone alkaline phosphatase (-14.5%, 95% CI: -26.2 to -3·0, P = 0.007), CTX (-66.3%, 95% CI: -74.0 to -56.4, P <0.001) and osteocalcin (-36.8%, 95% CI: -45.6 to -26.6, P <0.001). After 6 years, of the 35 NHYPO subjects with follow-up data, none developed overt hypoparathyroidism and only 15 (0.6%) subjects had persistent evidence of NHYPO. We also identified 86 subjects (3.6%) affected by hyperparathyroid hypercalcaemia. Conclusion: this is the first large population-based study to investigate NHYPO in older women. NHYPO is fairly common, not always persistent and is characterized by low bone turnover. 3. RESEARCH QUESTION Can PTH(1-34) treatment restore the calcium and phosphate balance and improve the quality of life in adult subjects with post-operative hypoparathyroidism? ABSTRACT Introduction: conventional therapy for hypoparathyroidism consists of calcium and calcitriol, but sometimes normal serum calcium cannot be maintained, and/or this approach might lead to nephrocalcinosis, nephrolithiasis, or renal insufficiency. The objective of the study was to investigate the effects of 6 months of PTH(1-34) treatment in adult subjects with postoperative hypoparathyroidism and to evaluate quality-of-life changes. Methods and design: this is an Italian multicentric 2-year prospective, open-label study that has included 42 subjects with surgical hypoparathyroidism (90% females, age range 34-77 y). The intervention included a twice-daily PTH(1-34) 20 mcg sc injection. At baseline and after 6 months of PTH(1-34) treatment, calcium and vitamin D supplementation requirements, serum calcium, phosphate, creatinine, alkaline phosphatase, uric acid, and 24-hour urinary calcium excretion were evaluated. Quality of life was evaluated by the Rand 36-Item Short Form Health Survey covering eight domains of physical and mental health. Results: the mean serum calcium levels significantly increased from baseline to 15 days (7.6 ± 0.6 vs 9.1 ± 0.9 mg/dL, P <.001) and remained stable until the end of the observational period, despite a significant reduction in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to the sixth month (P = .005 for the trend), whereas the alkaline phosphatase increased (P <.001). Data from the Rand 36-Item Short Form Health Survey showed a significant improvement in the mean scores of all eight domains (P <.001). Conclusion: this is the largest study that demonstrates the effectiveness of PTH(1-34) in the treatment of adult patients with postsurgical hypoparathyroidism, and it shows that PTH(1-34) may improve the mental and physical health in hypoparathyroid subjects. 4. RESEARCH QUESTION Can PTH(1-34) prevent the onset of hypocalcemia and shorten the duration of hospitalization in subjects with high risk of post-surgical after thyroidectomy? ABSTRACT Introduction: subjects undergoing thyroidectomy may experience severe hypocalcemia often requiring extended hospitalization with increased healthcare costs. Up to now, there are no studies evaluating the use of teriparatide for prevention of postoperative hypocalcemia. The objectives of this study are to evaluate whether teriparatide can prevent post-surgical hypocalcemia and shorten the hospitalization in subjects at high risk of hypocalcemia following thyroid surgery. Methods and design: this is a prospective Phase II Randomized Open Label Trial conducted in the Surgical ward of the University Campus Bio-Medico. 26 subjects (6 males, 20 females, mean age 53.4, SD 17.0) with iPTH <10 pg/ml 4 hours after thyroidectomy have been enrolled. Subjects have been randomized (1:1) to receive subcutaneous administration of 20 mcg of teriparatide every 12 hours until the discharge (treatment group) or to follow the standard clinical care (control group). The Main Outcome Measure were Adjusted serum calcium, duration of hospitalization, calcium/calcitriol supplementation. Results: treated patients had a lower risk of hypocalcemia than controls [RR 0.26 (95% CI:0.09- 0.723)]. The median duration of hospitalization was 3 days (IQR:1) in control subjects and 2 days (IQR:0) in treated subjects (P = 0.012). One month after discharge, 10 out of 13 subjects in the treatment group had stopped calcium carbonate supplements, while only 5/13 in the control group had discontinued calcium. The ANOVA for repeated measures showed a significant difference in calcium supplements between groups at one month visit (P = 0.04) as well as a significant difference between discharge and one month visit in the treatment group (P for interaction time group = 0.04). Conclusions: our findings suggest that Teriparatide may prevent post-surgical hypocalcemia, shorten the duration of hospitalization and reduce the need for calcium and vitamin D supplementation after discharge in high risk subjects after thyroid surgery.