Cinacalcet increases renal calcium excretion in PTHrP-mediated hypercalcemia: a case report.

BACKGROUND: In the acute setting, PTH-independent hypercalcemia is typically treated with anti-resorptive agents such as zoledronic acid or denosumab. When these agents are no longer able to control hypercalcemia, several case reports have shown the utility of cinacalcet. However, it is not known if cinacalcet can be effective in patients naïve to anti-resorptive therapy or how cinacalcet ameliorates the hypercalcemia. CASE PRESENTATION: A 47-year-old male with a history of alcohol-induced cirrhosis was admitted for left cheek bleeding and swelling from an infiltrative squamous cell carcinoma of the oral cavity. On admission, he was found to have an elevated albumin-corrected serum calcium of 13.6 mg/dL, a serum phosphorus of 2.2 mg/dL and an intact PTH of 6 pg/mL (normal 18-90) with a PTHrP of 8.1 pmol/L (normal < 4.3), consistent with PTHrP-dependent hypercalcemia. Aggressive intravenous saline hydration and subcutaneous salmon calcitonin were initiated, but his serum calcium remained elevated. Given tooth extractions scheduled for the next day and possible irradiation to the jaw in the near future, alternatives to antiresorptive therapy were sought. Cinacalcet was initiated at 30 mg twice daily then increased to 60 mg twice daily the following day. The albumin-corrected serum calcium level decreased from 13.2 to 10.9 mg/dL within 48 h. The fractional excretion of calcium increased from 3.7 to 7.0%. CONCLUSIONS: This case demonstrates the utility of cinacalcet for the treatment of PTHrP-mediated hypercalcemia without prior anti-resorptive therapy via increased renal clearance of calcium.

New Frontiers in Osteoporosis Therapy.

Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone-related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.

Osteoporosis and fractures in rheumatoid arthritis.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is associated with increased risk for osteoporotic fracture. We highlight RA-specific risk factors for bone mineral density (BMD) loss and fractures and considerations regarding the diagnosis and treatment of osteoporosis in patients with RA. RECENT FINDINGS: Anticitrullinated protein antibody (ACPA) positivity, although associated with low BMD in early RA, is not associated with accelerated BMD loss over time when compared to ACPA negative individuals. Studies have found reduced BMD in individuals on low doses of glucocorticoids (GCs). Poor functional status and frailty are additional important risk factors for low BMD and fractures. Heightened fracture risk in RA may be mitigated by tight disease control, and biologic therapies are associated with more stable BMD compared to nonbiologic therapies. Evidence-based guidelines specific for treating osteoporosis in patients with RA do not exist. Thus, treatment decisions are based on general osteoporosis guidelines, taking into account additional RA-specific risk factors. SUMMARY: Recent studies have advanced knowledge of RA-specific risk factors for BMD loss and fractures. Future studies applying these findings to modify established fracture risk algorithms as well as evaluating osteoporosis treatments in RA cohorts are needed to reduce the risk of disabling fractures in these patients.

The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics.

BACKGROUND: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. METHODS: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. RESULTS: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. CONCLUSIONS: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. TRIAL REGISTRATION: EUPAS16927, NCT01922440.

Mechanisms Underlying Normal Fracture Healing and Risk Factors for Delayed Healing.

PURPOSE OF REVIEW: Substantial advances have been made in understanding the biological basis of fracture healing. Yet, it is unclear whether the presence of osteoporosis or prior or current osteoporosis therapy influences the healing process or is associated with impaired healing. This review discusses the normal process of fracture healing and the role of osteoporosis and patient-specific factors in relation to fracture repair. RECENT FINDINGS: The definitive association of osteoporosis to impaired fracture healing remains inconclusive because of limited evidence addressing this point. eStudies testing anabolic agents in preclinical models of ovariectomized animals with induced fractures have produced mostly positive findings showing enhanced fracture repair. Prospective human clinical trials, although few in number and limited in design and to testing only one anabolic agent, have similarly yielded modestly favorable results. Interest is high for exploring currently available osteoporosis therapies for efficacy in fracture repair. Definitive data supporting their efficacy are essential in achieving approval for this indication.

Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism.

Parathyroid hormone (PTH)-related peptide (PTHrP) controls the pace of pre- and post-natal growth plate development by activating the PTH1R in chondrocytes, while PTH maintains mineral and skeletal homeostasis by modulating calciotropic activities in kidneys, gut, and bone. The extracellular calcium-sensing receptor (CaSR) is a member of family C, G protein-coupled receptor, which regulates mineral and skeletal homeostasis by controlling PTH secretion in parathyroid glands and Ca(2+) excretion in kidneys. Recent studies showed the expression of CaSR in chondrocytes, osteoblasts, and osteoclasts and confirmed its non-redundant roles in modulating the recruitment, proliferation, survival, and differentiation of the cells. This review emphasizes the actions of CaSR and PTH1R signaling responses in cartilage and bone and discusses how these two signaling cascades interact to control growth plate development and maintain skeletal metabolism in physiological and pathological conditions. Lastly, novel therapeutic regimens that exploit interrelationship between the CaSR and PTH1R are proposed to produce more robust osteoanabolism.

Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.

Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-ß and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.

A Case of Hypercalcemia and Overexpression of CYP27B1 in Skeletal Muscle Lesions in a Patient with HIV Infection After Cosmetic Injections with Polymethylmethacrylate (PMMA) for Wasting.

Foreign body-induced granuloma is an uncommon yet clinically significant cause of hypercalcemia. The molecular mechanisms are uncertain, although extrarenal calcitriol production has been proposed. We describe severe hypercalcemia associated with increased levels of plasma calcitriol in a patient with HIV and local granulomatous reaction 5 years after injection of polymethylmethacrylate (PMMA) as dermal filler for cosmetic body sculpting. Extensive evaluation revealed no identifiable cause of increased calcitriol levels. Nuclear imaging was remarkable for diffuse uptake in the subcutaneous tissues of the buttocks. Subsequent muscle biopsy and immunohistochemical staining showed strong local expression of CYP27B1 within histiocytes surrounding globules of PMMA. This case highlights an unfortunate complication of dermal fillers and shows that inflammatory cells can express high levels of CYP27B1 even without frank granulomas. The growing trend of body contour enhancement using injectable fillers should raise suspicion for this cause of hypercalcemia in clinical practice. Patients with HIV who receive this treatment for lipodystrophy or other cosmetic purposes may have increased susceptibility to hypercalcemia in the setting of underlying chronic inflammation. This may be a concern when changing anti-retroviral therapy, since alterations in levels of HIV viremia may initiate or contribute to worsening hypercalcemia.

Bone Mineral Density, Bone Turnover, and Systemic Inflammation in Non-cirrhotics with Chronic Hepatitis C.

BACKGROUND: Whether chronic HCV, a disease characterized by systemic inflammation, impacts bone mineral density (BMD) independent of cirrhosis is unknown. AIM: We aimed to evaluate the association between BMD, systemic inflammation, and markers of bone turnover in chronic HCV without cirrhosis. METHODS: Non-cirrhotics, 40-60 years old, with chronic HCV underwent measurement of: (1) BMD by dual-energy X-ray absorptiometry scan and (2) serum markers of systemic inflammation and bone turnover. By Chi-squared or t test, we compared those with normal versus low BMD. RESULTS: Of the 60 non-cirrhotics, 53 % were female and 53 % Caucasian. Mean (SD) age was 53.3 years (5.7), total bilirubin 0.7 mg/dL (0.3), creatinine 0.8 mg/dL (0.2), and body mass index 28.4 kg/m(2) (6.5). Low BMD was observed in 42 %: 30 % had osteopenia, 12 % had osteoporosis. Elevated tumor necrosis factor α, interleukin-6, and C-reactive protein levels were found in 26, 32, and 5 %, respectively, but did not differ by BMD group (p > 0.05). Patients with low BMD had higher serum phosphorus (4.1 vs. 3.5 mg/dL) and pro-peptide of type 1 collagen (P1NP; 73.1 vs. 47.5 ng/mL) [p < 0.05], but similar bone-specific alkaline phosphatase, serum C-telopeptide, and parathyroid hormone levels. CONCLUSIONS: Low BMD is prevalent in 40- to 60-year-old non-cirrhotics with chronic HCV, but not associated with systemic inflammatory markers. Elevated P1NP levels may help to identify those at increased risk of bone complications in this population. Chronic HCV should be considered a risk factor for bone loss, prompting earlier BMD assessments in both men and women.

Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial.

INTRODUCTION: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. METHODS: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. RESULTS: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. CONCLUSION: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04701203.

Chronic hypoparathyroidism is caused by inadequate parathyroid hormone (PTH) levels. Hypoparathyroidism is managed with conventional therapy (active vitamin D and calcium), but over time the disease itself and conventional therapy can increase the risk of medical complications including kidney problems. This study looked at how a new treatment for chronic hypoparathyroidism, palopegteriparatide (approved in the European Union under the brand name YORVIPATH^®), affects kidney function in adults in the PaTHway clinical trial. Participants were randomly assigned to receive palopegteriparatide or a placebo injection once daily along with conventional therapy. For both groups, clinicians used a protocol to eliminate conventional therapy while maintaining normal blood calcium levels. After 26 weeks, participants on placebo switched to palopegteriparatide. Ninety-five percent of participants were still enrolled in the PaTHway trial after 52 weeks. Of those, 86% had normal blood calcium levels and 95% did not need conventional therapy (not taking vitamin D and not taking therapeutic doses of calcium [> 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.

Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism.

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

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).

Progressive craniofacial bone loss after cosmetic surgery at the forehead.

We present the case of a 59-year-old woman with a history of plastic surgery at the forehead who complained of progressive indentations at the frontal skull. CT and MR scans revealed significant bone thinning, presenting as lytic skull lesions, which progressed over a period of 3 years. Biopsies were obtained from the lytic lesions and histology showed fibrotic tissue, synthetic residue of previous cosmetic procedure, and no evidence of infection or neoplasm. Progressive cranial bone resorption places the patient at increased risk for cerebral injury. This case highlights a potential complication after cosmetic facial surgery, with bony resorption resulting in both skull deformation and increased risk for cerebral injury.

Low cumulative disease activity is associated with higher bone mineral density in a majority Latinx and Asian US rheumatoid arthritis cohort.

OBJECTIVE: Prior studies have found conflicting results when evaluating the association between rheumatoid arthritis (RA) disease activity and bone mineral density (BMD). Whether or not cumulative RA disease activity is associated with BMD remains unanswered. METHODS: Data were from the University of California San Francisco RA Cohort from years 2006-2018. Those with BMD measures and at least two study visits prior to BMD measure were included in the study. The association between low cumulative disease activity, as measured by DAS28ESR, with the primary outcome of femoral neck BMD was assessed using multivariable linear regression. Sensitivity analyses were performed substituting CDAI for the disease activity measure as well as total hip and lumbar spine BMD as outcomes. RESULTS: 161 participants with RA were studied. The cohort was 62.4 ± 10.2 years old and 88% female. Hispanic/Latino (N = 73, 45%) and Asian (N = 59, 37%) were the most common racial/ethnic groups in our cohort. Mean RA duration was 10.5 ± 7.3 years and 83% were ACPA positive. Low disease activity was independently associated with higher femoral neck BMD compared to the moderate/high disease activity group (ß= 0.071 [95%CI: 0.021 to 0.122], p = 0.020). The relationship between low cumulative disease activity was similar when CDAI and other BMD sites were substituted in the multivariable models. CONCLUSION: Low cumulative disease activity as measured by DAS28ESR was associated with higher femoral neck BMD, independent of traditional osteoporosis risk factors (e.g., age, sex, BMI) in a unique RA cohort. Results were similar when evaluating cumulative low CDAI and other BMD sites.

Bone marrow adipose tissue composition and glycemic improvements after gastric bypass surgery.

Fracture risk is increased in type 2 diabetes, which may in part be due to altered bone marrow adiposity. Cross sectional studies have reported that people with type 2 diabetes have lower unsaturated BMAT lipid levels than people without diabetes, although there are limited data on longitudinal changes. We hypothesized that Roux-en-Y gastric bypass (RYGB), which dramatically improves glycemic status, would have differential effects on BMAT composition, with increases in the unsaturated lipid index in people with diabetes. Given reports that axial BMAT is responsive to metabolic stimuli while appendicular BMAT is stable, we hypothesized that BMAT changes would occur at the spine but not the tibia. We enrolled 30 obese women, stratified by diabetes status, and used magnetic resonance spectroscopy to measure BMAT at the spine in all participants, and the tibia in a subset (n = 19). At baseline, BMAT parameters were similar between those with and without diabetes, except tibial marrow fat content was lower in women with diabetes (97.4 % ± 1.0 % versus 98.2 % ± 0.4 %, p = 0.04). Six months after surgery, both groups experienced similar weight loss of 27 kg ± 7 kg. At the spine, there was a significant interaction between diabetes status and changes in both marrow fat content and the unsaturated lipid index (p = 0.02, p < 0.01 for differences, respectively). Women with diabetes had a trend towards a decline in marrow fat content (-4.3 % ± 8.2 %, p = 0.09) and increase in the unsaturated lipid index (+1.1 % ± 1.5 %, p = 0.02). In contrast, BMAT parameters did not significantly change in women without diabetes. In all women, changes in the unsaturated lipid index inversely correlated with hemoglobin A1c changes (r = -0.47, p = 0.02). At the tibia, there was little BMAT change by diabetes status. Our results suggest that vertebral BMAT composition is responsive to changes in glycemic control after RYGB.

Risk of Fracture Among Older Adults With Primary Hyperparathyroidism Receiving Parathyroidectomy vs Nonoperative Management.

Importance: Primary hyperparathyroidism (PHPT) contributes to the development and progression of osteoporosis in older adults. The effectiveness of parathyroidectomy for reducing fracture risk in older adults is unknown. Objective: To compare the incidence of clinical fracture among older adults with PHPT treated with parathyroidectomy vs nonoperative management. Design, Setting, and Participants: This was a population-based, longitudinal cohort study of all Medicare beneficiaries with PHPT from 2006 to 2017. Multivariable, inverse probability weighted Cox proportional hazards and Fine-Gray competing risk regression models were constructed to determine the association of parathyroidectomy vs nonoperative management with incident fracture. Data analysis was conducted from February 17, 2021, to September 14, 2021. Main Outcomes and Measures: The primary outcome was clinical fracture at any anatomic site not associated with major trauma during the follow-up period. Results: Among the 210 206 Medicare beneficiaries with PHPT (mean [SD] age, 75 [6.8] years; 165 637 [78.8%] women; 183 433 [87.3%] White individuals), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis, and 147 070 (70.0%) were managed nonoperatively. During a mean (SD) follow-up period of 58.5 (35.5) months, the unadjusted incidence of fracture was 10.2% in patients treated with parathyroidectomy. During a mean (SD) follow-up of 52.5 (33.8) months, the unadjusted incidence of fracture was 13.7% in patients observed nonoperatively. On multivariable analysis, parathyroidectomy was associated with lower adjusted rates of any fracture (hazard ratio [HR], 0.78; 95% CI, 0.76-0.80]) and hip fracture (HR, 0.76; 95% CI, 0.72-0.79). At 2, 5, and 10 years, parathyroidectomy was associated with adjusted absolute fracture risk reduction of 1.2% (95% CI, 1.0-1.4), 2.8% (95% CI, 2.5-3.1), and 5.1% (95% CI, 4.6-5.5), respectively, compared with nonoperative management. On subgroup analysis, there were no significant differences in the association of parathyroidectomy with fracture risk by age group, sex, frailty, history of osteoporosis, or meeting operative guidelines. Fine-Gray competing risk regression confirmed parathyroidectomy was associated with a lower probability of any fracture and hip fracture when accounting for the competing risk of death (HR, 0.84; 95% CI, 0.82-0.85; and HR, 0.83; 95% CI, 0.80-0.85, respectively). Conclusions and Relevance: This longitudinal cohort study found that parathyroidectomy was associated with a lower risk of any fracture and hip fracture among older adults with PHPT, suggesting a clinically meaningful benefit of operative management in this population.

Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review.

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 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).

Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop.

This clinical practice guideline addresses the prevention, diagnosis, and management of hypoparathyroidism (HypoPT) and provides evidence-based recommendations. The HypoPT task forces included four teams with a total of 50 international experts including representatives from the sponsoring societies. A methodologist (GG) and his team supported the taskforces and conducted the systematic reviews. A formal process following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and the systematic reviews provided the structure for seven of the guideline recommendations. The task force used a less structured approach based on narrative reviews for 20 non-GRADEd recommendations. Clinicians may consider postsurgical HypoPT permanent if it persists for >12 months after surgery. To predict which patients will not develop permanent postsurgical HypoPT, we recommend evaluating serum PTH within 12 to 24 hours post total thyroidectomy (strong recommendation, moderate quality evidence). PTH > 10 pg/mL (1.05 pmol/L) virtually excludes long-term HypoPT. In individuals with nonsurgical HypoPT, genetic testing may be helpful in the presence of a positive family history of nonsurgical HypoPT, in the presence of syndromic features, or in individuals younger than 40 years. HypoPT can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataracts, seizures, cardiac arrhythmias, ischemic heart disease, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory indices. In patients with chronic HypoPT, the panel suggests conventional therapy with calcium and active vitamin D metabolites as first-line therapy (weak recommendation, low-quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. © 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).

Sporadic Primary Hyperparathyroidism.

Sporadic primary hyperparathyroidism is a common endocrinopathy, particularly afflicting postmenopausal women and both African American men and women. Although classic signs and symptoms of the disease are well appreciated and described, because of the ease and availability and low threshold for screening, the disorder often is diagnosed in patients who are minimally symptomatic or asymptomatic. Surgery conducted by experienced endocrine surgeons has a high cure rate, particularly if guided by concordant imaging. In patients who cannot safely undergo surgery or who fail to be cured, medical therapy with the oral calcimimetic cinacalcet is a validated option for controlling serum calcium levels.