Bone metabolism, density, and geometry in postmenopausal women with vitamin D insufficiency: a cross-sectional comparison of the effects of elevated parathyroid levels.

Increased levels of parathyroid hormone (PTH) may have adverse effects on bone health. In a cross-sectional design, we investigated this hypothesis among 102 postmenopausal vitamin D insufficient women. Elevated PTH was associated with altered bone geometry, decreased bone mineral density in the spine, and increased bone turnover. INTRODUCTION: In vitamin D insufficiency, elevated parathyroid hormone (PTH) levels may contribute to adverse effect on bone. We assessed effects of PTH responses to vitamin D insufficiency on bone metabolism, density, and geometry. METHODS: Using a cross-sectional design, we investigated 102 healthy postmenopausal women with low 25-hydroxy-vitamin D (< 50 nmol/L) levels, who had either secondary hyperparathyroidism with elevated PTH levels (> 6.9 pmol/L, N = 51) or normal PTH levels (N = 51). Bone mineral density (BMD) and bone geometry were assessed by Dual-Energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT) and high-resolution peripheral QCT (HRpQCT) scans. Bone metabolism was assessed by biochemistry including bone turnover markers. RESULTS: Levels of 25(OH)D were 38 (IQR 31-45) nmol/L with no differences between groups. PTH levels were 8.5 (IQR 7.5-9.5) in women with SHPT and 5.2 (4.4-6.6) pmol/L in women with normal PTH (p < 0.001). BMI and eGFR did not differ between groups. SHPT was associated with lower total- and trabecular bone area, lower cortical perimeter, and increased cortical area in tibia and radius. SHPT was associated with a lower weight-adjusted BMD at the lumbar spine (p < 0.05). High compared to normal PTH levels were associated with significantly lower plasma levels of 1,25(OH)2D, phosphate, but higher levels of osteocalcin and borderline higher levels of CTx. PTH correlated to osteocalcin and CTx. CONCLUSIONS: High PTH levels are associated with altered bone geometry, increased bone turnover, and reduced BMD at the spine. Whether an increased cortical thickness with a lower trabecular volume is an effect of PTH or not needs further elucidations.

Health-related quality of life in patients with nonsurgical hypoparathyroidism and pseudohypoparathyroidism.

OBJECTIVE: Nonsurgical hypoparathyroidism (NS-HypoPT) and pseudohypoparathyroidism (PHP) are rare diseases, with a prevalence of 2/100.000 and 1/100.000, respectively. Only few studies on Quality of Life (QoL) among patients with Ns-HypoPT and PHP are available. We aimed to investigate the QoL among patients with Ns-HypoPT and PHP including information about education. DESIGN: A cohort study with patients identified from a previously epidemiological study. PATIENTS: Fifty seven patients with Ns-HypoPT and 30 patients with PHP. MEASUREMENTS: The well-validated questionnaires SF-36v2 and WHO-5 Well Being Index. Results compared to norm-based material, disease-specific norm-based material and patients with postsurgical HypoPT RESULTS: SF36v2 showed a significantly reduced score in all eight subdomains in patients with NS-HypoPT compared with a norm-based population. PHP patients scored lower in five subdomains. Females were more affected than males. Compared with postsurgical HypoPT, Ns-HypoPT and PHP are compatible at most domains. At the domains Physical Function, Social Function and Mental Health, Ns-HypoPT and PHP patients scored significantly lower (Pall  < .05). At the Mental Component Score, patients with Ns-HypoPT had a lower score compared with postsurgical HypoPT (P < .01). The overall WHO-5 Well Being Index score was comparable between groups (P = .45). No differences were seen comparing patients with postsurgical HypoPT and Ns-HypoPT (P = .68) or postsurgical HypoPT and PHP (P = .67). A WHO-5 score below 28 indicates depression (NS-HypoPT=7; PHP=3, P = .71), whereas a score between 28-50 suggesting poor emotional well-being (NS-HypoPT=19; PHP=5, P = .13). The remaining patients scored above 50 suggesting well-being. CONCLUSION: QoL is impaired equally among patients with Ns-HypoPT and PHP.

Effects of PTH(1-84) therapy on muscle function and quality of life in hypoparathyroidism: results from a randomized controlled trial.

UNLABELLED: The effects of treatment with 100 µg parathyroid hormone (PTH) (1-84) or an identical placebo on muscle function and quality of life (QoL) was studied in hypoparathyroid patients. At baseline, we found reduced QoL but no myopathy in the patients. Six months of treatment did not improve QoL, and muscle strength decreased slightly. INTRODUCTION: A reduced quality of life (QoL) and myopathy that may be due to the absence of PTH have been reported in patients with hypoparathyroidism (hypoPT). METHODS: Sixty-two patients with chronic hypoPT were randomized to 6 months of treatment with either PTH(1-84) 100 µg/d s.c. or placebo, given as add-on therapy to conventional treatment. Muscle function and postural stability were investigated using a dynamometer chair, a stadiometer platform, the repeated chair stands test, the timed up and go test, and electromyography. QoL was assessed using the 36-item Short Form Health Survey and the WHO-5 Well-Being Index. RESULTS: The mean age of the patients was 52 ± 11 years, and 85 % were females. At baseline, QoL was significantly reduced in comparison with norm-based scores. Compared with placebo, PTH did not improve QoL or muscle function. Rather, max force production decreased significantly by 30 % at elbow flexion in the PTH group compared with the placebo group. Moreover, there was a nonsignificant trend for muscle strength to decrease in the upper extremities and on knee extension in response to PTH. Treatment did not affect postural stability. Electromyography showed a slight decrease in the duration of motor unit potentials in the PTH group, indicating a tendency toward myopathy, which, however was not symptomatic. CONCLUSIONS: Overall, our data do not support an immediate beneficial effect of PTH replacement therapy on muscle function or QoL. A high frequency of hypercalcemia among our patients may have compromised the potential beneficial effects of reversing the state of PTH insufficiency.

Melatonin and the skeleton.

Melatonin may affect bone metabolism through bone anabolic as well as antiresorptive effects. An age-related decrease in peak melatonin levels at nighttime is well documented, which may increase bone resorption and bone loss in the elderly. In vitro, melatonin reduces oxidative stress on bone cells by acting as an antioxidant. Furthermore, melatonin improves bone formation by promoting differentiation of human mesenchymal stem cell (hMSC) into the osteoblastic cell linage. Bone resorption is reduced by increased synthesis of osteoprogeterin (OPG), a decoy receptor that prevents receptor activator of NK-κB ligand (RANKL) in binding to its receptor. Moreover, melatonin is believed to reduce the synthesis of RANKL preventing further bone resorption. In ovariectomized as well as nonovariectomized rodents, melatonin has shown beneficial effects on bone as assessed by biochemical bone turnover markers, DXA, and µCT scans. Furthermore, in pinealectomized animals, bone mineral density (BMD) is significantly decreased compared to controls, supporting the importance of sufficient melatonin levels. In humans, dysfunction of the melatonin signaling pathway may be involved in idiopathic scoliosis, and the increased fracture risk in nighttime workers may be related to changes in the circadian rhythm of melatonin. In the so-far only randomized study on melatonin treatment, no effects were, however, found on bone turnover markers. In conclusion, melatonin may have beneficial effects on the skeleton, but more studies on humans are warranted in order to find out whether supplementation with melatonin at bedtime may preserve bone mass and improve bone biomechanical competence.

PTH replacement therapy of hypoparathyroidism.

Hypoparathyroidism is characterized by hypocalcemia with inappropriately low parathyroid hormone (PTH) levels. Bone turnover is abnormally low and bone mineral density (BMD) is typically increased. Plasma calcium levels can be normalized by treatment with calcium supplements and vitamin D analogs, but bone turnover remains low and patients complain of a reduced quality of life (QoL). During recent years, a number of studies have shown that PTH replacement therapy (PTH-RT) may maintain calcium levels within the normal range, while the need for calcium and vitamin D supplements is reduced. In the initial response to subcutaneous PTH injections once or twice daily, bone turnover is overstimulated. BMD increases in cancellous bone, but decreases in cortical bone due to an increased porosity. Microcomputed tomography scans and histomorphometric studies on bone biopsies have shown changes similar to the well-known bone anabolic effects of PTH treatment in osteoporosis rather than a normalization of bone remodeling balancing the anabolic and catabolic effects of PTH. Most recently, continuous PTH delivery by pump was shown to increase the levels of bone markers into the normal range (without overstimulation of bone turnover) and with a normalization of renal calcium excretion. As PTH has a short plasma half-life, these findings indicate that exposure to PTH once or twice daily is not sufficient to reestablish a calcium homeostasis and bone metabolism that resembles normal physiology. Further studies should assess the effects of continuous PTH exposure by pump delivery (or multiple daily injections) on BMD and bone histology, as well as the effects of PTH-RT on indices of QoL.