Pseudohypoparathyroidism type 1 B mimicking Fahr’s disease in a 28‐year‐old female: A case report

In virtue of precise clinical history, physical examinations, and biochemical/radiological investigations, pseudohypoparathyroidism can be effectively diagnosed, and its types can be differentiated even without exorbitant tests.     

Calcium Bioavailability and Parathyroid Hormone Acute Changes after Oral Intake of Dairy and Nondairy Products in Healthy Volunteers

This study was designed to compare calcium bioavailability and serum parathyroid hormone acute changes after oral intake of 500 mg of elemental calcium from liquid milk, yogurt, calcium-citrate-enriched powdered milk or a calcium carbonate pill; or after intake of soybean imitation-milk. After a 12-h fast, blood samples were drawn both at baseline and 1, 2, 3 and 4 h after an oral intake of the above-mentioned products, which were ingested together with a light neutral breakfast. The administration order of the study products was randomly assigned to each of 19 healthy young volunteers (11 females, 8 males). The baseline serum concentrations of ionized calcium, phosphorus and intact parathyroid hormone (iPTH) were normal. Calcium-citrate-enriched powdered milk induced a significant increase in serum ionized calcium (p<0.001) and a significant and continuous decrease in serum iPTH concentration (p<0.001). Yogurt and the calcium carbonate pill induced a similar but less significant effect, increasing serum ionized calcium (p<0.05) and decreasing serum iPTH (p<0.01). Liquid milk only induced a significant change in serum ionized calcium and iPTH concentration during the first 2 h; this effect was lost during the following 2 h. In conclusion, our study suggests the possibility that the addition of calcium citrate to powered milk may improve calcium bioavailability and enhance the inhibitory effect on serum iPTH in the assayed conditions. Received: 15 September 1998 / Accepted: 15 January 1999     

Anabolic Bone Stimulus Requires a Pre-Exercise Meal and 45-Minute Walking Impulse of Suprathreshold Speed-Enhanced Momentum to Prevent or Mitigate Postmenopausal Osteoporosis within Circadian Constraints

Osteoporosis currently afflicts 8 million postmenopausal women in the US, increasing the risk of bone fractures and morbidity, and reducing overall quality of life. We sought to define moderate exercise protocols that can prevent postmenopausal osteoporosis. Our previous findings singled out higher walking speed and pre-exercise meals as necessary for suppression of bone resorption and increasing of markers of bone formation. Since both studies were amenable to alternate biomechanical, nutritional, and circadian interpretations, we sought to determine the relative importance of higher speed, momentum, speed-enhanced load, duration of impulse, and meal timing on osteogenic response. We hypothesized that: (1) 20 min of exercise one hour after eating is sufficient to suppress bone resorption as much as a 40-min impulse and that two 20 min exercise bouts separated by 7 h would double the anabolic effect; (2) early morning exercise performed after eating will be as effective as mid-day exercise for anabolic outcome; and (3) the 08:00 h 40-min. exercise uphill would be as osteogenic as the 40-min exercise downhill. Healthy postmenopausal women, 8 each, were assigned to a no-exercise condition (SED) or to 40- or 20-min exercise bouts, spaced 7 h apart, for walking uphill (40 Up and 20 Up) or downhill (40 Down and 20 Down) to produce differences in biomechanical variables. Exercise was initiated at 08:00 h one hour after eating in 40-min groups, and also 7 h later, two hours after the midday meal, in 20-min groups. Measurements were made of CICP (c-terminal peptide of type I collagen), osteocalcin (OC), and bone-specific alkaline phosphatase (BALP), markers of bone formation, and of the bone resorptive marker CTX (c-terminal telopeptide of type 1 collagen). The osteogenic ratios CICP/CTX, OC/CTX, and BALP/CTX were calculated. Only the 40-min downhill exercise of suprathreshold speed-enhanced momentum, increased the three osteogenic ratios, demonstrating the necessity of a 40-min, and inadequacy of a 20-min, exercise impulse. The failure of anabolic outcome in 40-min uphill exercise was attributed to a sustained elevation of PTH concentration, as its high morning elevation enhances the CTX circadian rhythm. We conclude that postmenopausal osteoporosis can be prevented or mitigated in sedentary women by 45 min of morning exercise of suprathreshold speed-enhanced increased momentum performed shortly after a meal while walking on level ground, or by 40-min downhill, but not 40-min uphill, exercise to avoid circadian PTH oversecretion. The principal stimulus for the anabolic effect is exercise, but the prerequisite for a pre-exercise meal demonstrates the requirement for nutrient facilitation.     

Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein–coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration–approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and β-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq^± and Arrb1^−/− mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

A total of ∼15% of childbearing–age couples are infertile, and male infertility accounts for nearly 50% of this sterility. Currently, male infertility is not only a personal problem but also becomes a public health issue (1–3). Epididymitis and orchitis, which are inflammatory diseases of the epididymis and testis, respectively, are estimated to account for 6 to 15% of male infertility and thus have attracted increasing attention in recent years (4–6). The current treatment of epididymitis and orchitis mainly relies on antibiotics since the inflammations were commonly caused by bacteria-induced infections. However, antibiotic therapies are known to cause undesired adverse effects. In addition, infection by viruses, such as mumps virus (MuV), cytomegalovirus, and herpes simplex virus, could also lead to epididymitis and orchitis, which are insensitive to regular antibiotic therapies (4, 7, 8). Therefore, novel therapeutic strategies for threating epididymitis and orchitis are needed.The G protein–coupled receptors (GPCRs) are the largest family of membrane proteins with wide-ranging expression and physiologic functions (9–11). Currently, GPCRs account for ∼30% of drug targets with clinical usage, but the physiological and pathological functions of the majority of GPCRs in the male reproduction system are still undefined (3, 12). Therefore, the characterization of functions of GPCRs involved in the regulation of inflammatory responses in the epididymis and testis may provide novel clues for treatments of epididymitis and orchitis. Mammalian GPCR are grouped into five families including Rhodopsin (Class A), Secretin (Class B1), Adhesion (Class B2), Glutamate (Class C), and Frizzled (Class F) (12, 13). The secretin family GPCR, consisting of 15 members, are peptide receptors that bind important endogenous peptide hormones (14–16). The secretin family GPCR and their cognate peptide ligands are implicated as drug targets in many pathologies, such as migraine, cardiovascular disease, diabetes, psychiatric disorders, neurodegeneration, osteoporosis, and inflammation (15–17). Among them, the type 1 parathyroid hormone receptor (PTH1R) primarily mediates skeletal development, bone turnover, and calcium homeostasis through interacting with two endogenous polypeptide ligands, parathyroid hormone (PTH) and PTH-related protein (PTHrP) (18, 19). PTH1R has been found to play an important role in many pathologies, such as osteoporosis, hypoparathyroidism, and cancer-associated hypercalcemia and cachexia (20, 21). Recent RNA sequencing results suggested a high expression of PTH1R in spermatozoa, implying a regulatory role of this receptor in the male reproductive system (22). However, the detailed functions and potential underlying mechanisms still remain unknown.In the present study, we found that PTH1R and its two endogenous ligands, PTHrP and PTH, were expressed in the Leydig cells of testis as well as epididymal epithelial cells. Both messenger RNA (mRNA) and protein levels of PTH1R and its ligands were down-regulated in the testis and epididymis upon MuV- or lipopolysaccharide (LPS)-induced inflammation. Interestingly, abaloparatide (ABL), which is an agonist of PTH1R and a Food and Drug Administration (FDA)–approved drug for postmenopausal osteoporosis (23), significantly alleviated MuV- or LPS-induced inflammation in the testis and epididymis and also enhanced sperm motility of mice. Further studies using Gnaq^± and Arrb1^−/− mice models and cellular approaches elucidated the mechanisms underlying the regulatory role of the PTH1R in the testis and epididymis. Our findings suggest that endogenous PTH1R signaling plays an important immunoregulatory role in the male reproduction system, and PTH1R is a potential therapeutic target for the treatment of epididymitis and orchitis.     

Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3–10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

New directions in the treatment of hypoparathyroidism

Treatment of chronic hypoparathyroidism remains a therapeutic challenge. In three quarters of cases, this endocrine disorder arises as a consequence of neck surgery, but it can also present in other disease settings, for example, in rare genetic disorders. Conventional standard of care treatment is based on oral administration of calcium and vitamin D. However, a significant proportion of patients remain uncontrolled biochemically under this treatment, with persistent clinical symptoms that affect quality of life. Administration of parathyroid hormone (PTH) in more recent times has encountered the problem of the short half-life of the hormone, which necessitates multiple daily injections or continuous subcutaneous administration controlled by a pump. Recently, progress in understanding the pathophysiology of hypoparathyroidism has opened the possibility of new therapeutic approaches using longer-acting forms of PTH, PTH receptor analogs or, more recently, calcilytic agents. These are the subjects of current clinical trials, with encouraging results. However, their possible future use will depend on their long-term impacts on bone metabolism and renal function, which remain to be determined.     

Uremic leontiasis ossea: distinctive imaging features allow differentiation from other clinical causes of leontiasis ossea

Skeletal changes are a common complication in patients with chronic kidney disease and traditionally labelled as renal osteodystrophy. Uremic leontiasis ossea is a rare and severe form of renal osteodystrophy with characteristic overgrowth of the craniofacial bones. Imaging, in particular computed tomography, is valuable for the diagnosis and management of such rare condition. Uremic leontiasis ossea has distinctive imaging features with significant overgrowth of the jaw and characteristic internal serpiginous tunneling. The recognition of its radiological appearance and abrupt management are essential to avoid its devastating esthetic and functional impairments.     

血液透析患者动静脉内瘘血管壁改变与钙磷代谢的相关性研究

【摘要】 目的 探讨维持性血液透析患者动静脉内瘘血管壁改变与钙磷代谢和甲状旁腺激素（PTH）的相关性，为临床血液透析患者钙磷代谢紊乱的调节提供依据。方法 纳入2013年1月至2015年12月于我院住院行动静脉内瘘手术的维持性血液透析患者共32例，收集所有患者的基本资料及实验室检查结果，包括性别、年龄、原发病、透析年龄、总胆固醇（CHOL）、HDL、LDL、TG、ALB、钙、磷、PTH的检测结果。所有患者在手术中留取少许动静脉内瘘动脉端血管标本进行分析。根据患者血清PTH的水平将其分为甲组（PTH＜400 pg/ml）和乙组（PTH≥400 pg/ml），比较两组患者血管壁的厚度及血清钙磷代谢情况。结果 乙组患者血管内膜的厚度（IT）大于甲组患者，差异具有统计学意义（378±148 vs. 602±241，P＝0003 ）。乙组患者发生血管内膜厚度≥60 μm的风险是甲组的8倍（CI：127~6261，P＜0005），两组患者血管钙化情况比较差异无统计学意义（P=0862）。回归分析提示PTH水平是患者血管壁增厚的独立危险因素（r=0653，P＜005）。结论 维持性血液透析患者血管厚度与血清PTH水平密切相关，高PTH是患者血管损伤的独立危险因素。     

Genotype-phenotype analysis of selective failure of tooth eruption—A systematic review

Tooth eruption is an important and unique biological process during craniofacial development. Both the genetic and environmental factors can interfere with this process. Here we aimed to find the failure pattern of tooth eruption among five genetic diseases. Both systematic review and meta-analysis were used to identify the genotype–phenotype associations of unerupted teeth. The meta-analysis was based on the characteristics of abnormal tooth eruption in 223 patients with the mutations in PTH1R, RUNX2, COL1A1/2, CLCN7, and FAM20A respectively. We found all the patients presented selective failure of tooth eruption (SFTE). Primary failure of eruption patients with PTH1R mutations showed primary or isolated SFTE1 in the first and second molars (59.3% and 52% respectively). RUNX2 related cleidocranial dysplasia usually had SFTE2 in canines and premolars, while COL1A1/2 related osteogenesis imperfecta mostly caused SFTE3 in the maxillary second molars (22.9%). In CLCN7 related osteopetrosis, the second molars and mandibular first molars were the most affected. While FAM20A related enamel renal syndrome most caused SFTE5 in the second molars (86.2%) and maxillary canines. In conclusion, the SFTE was the common characteristics of most genetic diseases with abnormal isolated or syndromic tooth eruption. The selective pattern of unerupted teeth was gene-dependent. Here we recommend SFTE to classify those genetic unerupted teeth and guide for precise molecular diagnosis and treatment.