The increased areal BMD values by DXA at the spine and hip sites are in accordance with data described in other hypoparathyroid cohorts [5–7, 25–29]. Increased BMD has been observed in patients with postsurgical, autoimmune, and idiopathic HypoPT on long-term treatment with calcium and vitamin D [3]. Rubin et al [5] evaluated 33 patients with HypoPT, including ten postmenopausal women, and found higher BMD Z-scores than in control subjects: + 2.2 SD at the lumbar spine (LS), + 1.1 SD at the total hip (TH) and + 1.3 SD at the femoral neck (FN). Sikjaer et al described positive BMD Z- scores in 62 hypoparathyroid patients at all DXA sites, of whom 86% were females and had a mean age of 52 years [25]. In general, BMD is increased at all skeletal sites, with the greatest T- or Z-scores observed at the lumbar spine, similar to our findings. Although the majority of our patients were postmenopausal women (78%), the mean BMD Z-scores were equal to or higher than + 1 SD. These findings may suggest a protective feature of HypoPT against postmenopausal bone loss [3]
The increased Ct. BMD at both the radius and tibia in our patients, compared with healthy subjects, is also consistent with few previously published data using HR-pQCT in HypoPT. Cusano et al studied bone microstructure of sixty hypoparathyroid subjects, thirteen of them were postmenopausal women (27%). Study population had a mean age of 46 years and was compared with previously published data from a healthy population. Compared with the control group, hypoparathyroid subjects had increased cortical density at the radius and tibia in all age and sex subgroups, which was similar to our results. Other changes were seen only in some subgroups, as a reduction in cortical thickness at both skeletal sites only in postmenopausal women. The same occurred in trabecular parameters: there was an increase in trabecular number in HypoPT women under 40 years and a decrease in trabecular separation in premenopausal women at the tibia but not at the radius. The trabeculae tended to be thinner only at the tibia in HypoPT women [4]. On the other hand, in a study of patients with non-surgical hypoparathyroidism, changes for overall patients were mainly seen in trabecular bone, as increased trabecular number at both the radius and the tibia. Elevated cortical density was only seen at the tibia in postmenopausal women [8]. Chen and colleagues described an increase in cortical volumetric density and cortical thickness in the forearm of nine HypoPT women compared with thirty-six women with primary hyperparathyroidism and one hundred healthy controls, using peripheral quantitative computed tomography [29].
Our study population included 21 postmenopausal women (78%), and we still found positive Z-scores at DXA at all sites. These differences could be attributed to increased cortical vBMD, as trabecular vBMD was not higher than in controls. Bone microstructure at both compartments (Ct.Th, Tb.N, Tb.Th, Tb.Sp and BV/TV) were similar in HypoPT and controls.
Body weight (and BMI) tended to be higher in HypoPT, although the difference did not reach statistical significance. We cannot rule out some influence of the weight-bearing effect to the increased BMD, mostly at the hip and distal tibia. However, DXA and HR- pQCT bone parameters were not associated with BMI.
There are limited data on fracture risk for hypoparathyroid patients, and studies show controversial results. Fujiyama et al studied thirty-three postmenopausal patients who underwent total thyroidectomy. According to fasting serum PTH, thirteen were classified as hypoparathyroid and twenty as having normal parathyroid function. The incidence of spinal deformity, based on radiographic findings, was three times lower in hypoparathyroid patients than in controls [10]. Mendonça and colleagues found increased morphometric vertebral fractures in sixteen postmenopausal postsurgical hypoparathyroid women compared with seventeen healthy female controls in a small cross-sectional study. Furthermore, six hypoparathyroid patients showed multiple vertebral fractures vs. only two in the control group [11]. Another cross-sectional study found increased morphometric vertebral fracture in one hundred and four patients with
idiopathic HypoPT vs sixty-four normative controls. Vertebral fractures were seen in 18.3% of patients with idiopathic HypoPT vs 4.7% of controls. Twelve patients had grade II vertebral fractures, and multiple fractures were observed in eleven patients vs. none in the control group [12].
Two longitudinal population-based studies by Underbjerg and colleagues showed no difference in vertebral and overall fractures between subjects with HypoPT and controls and reported that the risk for upper extremity fractures was lower in postsurgical patients and increased in nonsurgical HypoPT for unknown reasons [13 14]. Using data linkage from regional datasets, Vadiveloo et al compared hypoparathyroid patients with five age- and sex-matched controls from the general population and found no increased risk of fractures in postsurgical or nonsurgical disease [15]. These studies did not evaluate morphometric vertebral fractures, as vertebral imaging was not obtained. Cipriani et al studied fifty postmenopausal women with chronic postsurgical HypoPT and forty healthy age-matched postmenopausal women. There was a 16% prevalence of vertebral fracture in the HypoPT group and 7.5% in the control group assessed by VFA. Among fractured HypoPT women, five (62.5%) had a grade 1 wedge and two (25%) had a grade 2 wedge fracture. The 10-year probability of fracture, using FRAX tool, was not above accepted threshold values in both groups. However, when FRAX was assessed without femoral neck BMD, HypoPT group tended to present higher values than control group (8.2 ± 5.7 for major fractures and 2.6 ± 2.9 for hip fractures vs 6.8 ± 4.4 and 2.1 ± 2.4, respectively; p = 0.06). There were no differences between both groups when FRAX values were assessed with femoral neck BMD. [16]. In our study, patients had a low prevalence of clinical and morphometric vertebral fractures, as well as low fracture risk calculated by the FRAX tool and the NOGG calculator. However, of the two patients with a vertebral fracture, one patient had grade 2 obesity and the other patient was a current smoker. These characteristics may affect bone health, but it is important to mention the low number of fractures and low fracture risk in a population composed mostly of postmenopausal women.
The increase in serum levels of FGF23 may be associated with hyperphosphatemia seen in these patients. We observed that even in the presence of higher levels of FGF23 compared to healthy subjects, patients had TPR > 90% [19]. Although FGF23 is considered a phosphaturic hormone, this effect was not observed in the absence of PTH in this cohort. Both PTH and FGF23 regulate phosphate excretion through their actions on sodium-phosphate cotransporters in the proximal tubule. The interaction between these phosphaturic hormones is not fully understood. Some authors suggest that although FGF23 is one of the main regulators of urinary phosphate excretion, the existence of sufficient PTH is necessary for the full phosphaturic effect of FGF23 [30].
Rupp et al observed, in a large cross-sectional study, that FGF23 levels correlated significantly with trabecular bone microarchitecture, while no significant correlation was found with cortical bone parameters in osteoporotic patients [31]. There was no statistically significant correlation between FGF23 levels and bone parameters of DXA and HR-pQCT in our study. We also observed that circulating markers of bone formation (P1NP) and bone resorption (CTX) were lower than normative previously published data [20, 21]. This is in accordance with previous studies that demonstrated suppression of bone turnover biomarkers in patients with HypoPT. Rubin et al measured bone turnover markers in 64 hypoparathyroid subjects (48 women and 16 men) who were treated with calcium and vitamin D. Circulating markers of bone formation (P1NP, bone-specific alkaline phosphatase and osteocalcin) and bone resorption (CTX) were in the lower half of the normal range [32]. Gafni and colleagues showed suppressed levels of bone-specific alkaline phosphatase, osteocalcin and 24-hour urine collagen cross-linked N-telopeptide in 5 patients with either idiopathic or postsurgical HypoPT [ 33].
Our study is limited due to its cross-sectional design and small sample size, but the rarity of HypoPT should be considered. Additionally, mild fractures were not included in our analysis, but they are less relevant in predicting future fractures.
In summary, we demonstrated that patients with HypoPT have increased areal BMD by DXA at both the spine and hip, probably due to an increase in cortical density shown by HR-pQCT. We did not find an increased fracture risk or fracture prevalence, and further longitudinal studies are needed to confirm our results.