New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases.

BACKGROUND: Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings. AIMS: To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10th Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023. OUTCOMES: Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas. CONCLUSIONS: Assessing the status of the vitamin D/PTH axis and using vitamin D and PTH as therapeutic agents is mandatory in several endocrine-related bone metabolic conditions.

PTH and adiposity.

Although PTH is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism.

Parathyroid hormone controls skeletal and circulating calcium levels. Its secretion by the 4 parathyroid glands is regulated primarily by the concentration of the ionized calcium level. The other major target organ for parathyroid hormone is the kidney where it conserves filtered calcium by effects on the renal tubules. While bone and the kidney are indisputably the main target organs for PTH, recent studies are pointing to systems and organs that can be shown also to respond to PTH. One of these systems that PTH appears to target is fat cells, an important storehouse for energy. This review summarizes what is known about PTH's effects to stimulate the production of energy from fat cells when present in excess or to reduce the production of energy when deficient.

Massive 4-Gland Parathyroid Hyperplasia Initially Detected as a Parathyroid Adenoma.

Parathyroid adenoma (PA) and parathyroid hyperplasia (PH) are common causes of primary hyperparathyroidism (PHPT), for which the only definitive treatment is surgery. Abnormalities in the parathyroid glands can be identified with various imaging modalities including ultrasound (US), sestamibi scan (MIBI), 4-dimensional computed tomography (4D-CT), and positron emission tomography/computed tomography (PET/CT). While it is not uncommon for parathyroid pathology to be undetected on imaging, this is more typical of low-volume hyperplasia and smaller-sized adenomas. We present the case of a 65-year-old man with PHPT who initially had a solitary parathyroid mass detected by US, but who was ultimately discovered to have massive PH with hyperplastic glands not visualized on US or MIBI. This atypical presentation may help guide providers in decisions on ordering and interpreting various imaging modalities for patients with PHPT. In this case, 4D-CT was the only modality in which large hyperplastic glands were identified, suggesting superior sensitivity. This case also highlights the importance of intraoperative parathyroid hormone testing to aid in diagnostic prediction.

Proceedings of the 2023 Santa Fe Bone Symposium: Progress and Controversies in the Management of Patients with Skeletal Diseases.

The Santa Fe Bone Symposium (SFBS) held its 23rd annual event on August 5-6, 2023, in Santa Fe, New Mexico, USA. Attendees participated in-person and remotely, representing many states and countries. The program included plenary presentations, panel discussions, satellite symposia, a Project ECHO workshop, and a session on healthcare policy and reimbursement for fracture liaison programs. A broad range of topics were addressed, including transitions of osteoporosis treatments over a lifetime; controversies in vitamin D; update on Official Positions of the International Society for Clinical Densitometry; spine surgery and bone health; clinical applications of bone turnover markers; basic bone biology for clinicians; premenopausal-, pregnancy-, and lactation-associated osteoporosis; cancer treatment induced bone loss in patients with breast cancer and prostate cancer; genetic testing for skeletal diseases; and an update on nutrition and bone health. There were also sessions on rare bone diseases, including managing patients with hypophosphatasia; treatment of X-linked hypophosphatemia; and assessment and treatment of patients with hypoparathyroidism. There were oral presentations of abstracts by endocrinology fellows selected from those who participated in the Santa Fe Fellows Workshop on Metabolic Bone Diseases, held the 2 days prior to the SFBS. These proceedings of the 2023 SFBS present the clinical highlights and insights generated from many formal and informal discussions in Santa Fe.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

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.

The Clinical and Skeletal Effects of Long-Term Therapy of Hypoparathyroidism With rhPTH(1-84).

Hypoparathyroidism (HypoPT) is a disorder characterized by hypocalcemia, low or absent parathyroid hormone (PTH) levels, reduced bone remodeling, and high areal bone mineral density (aBMD). PTH is a therapeutic option, yet data on the prolonged clinical and skeletal effects of PTH treatment are limited. We tracked annual daily doses of calcium and active vitamin D supplements, calciotropic biochemistries, estimated glomerular filtration rate (eGFR), and aBMD measurements in 27 HypoPT patients (16 postsurgical, 11 nonsurgical) who were treated with recombinant human PTH(1-84) [rhPTH(1-84)] for at least 8 (n = 27) and up to 12 (n = 14) years. We also performed high-resolution-peripheral quantitative computed tomography (HRpQCT) imaging and report results at baseline, 5, 8, and 12 years of rhPTH(1-84) treatment. With prolonged use of rhPTH, reductions in the need for supplemental calcium and active vitamin D were maintained. The eGFR did not decline. Serum calcium was maintained within the lower limit of the normal range. aBMD by dual-energy X-ray absorptiometry (DXA) showed an increase at the lumbar spine and a decrease at the distal 1/3 radius. By HRpQCT, cortical volumetric BMD (vBMD) at the tibia decreased at year 5: -20.0% ± 1.5%. The magnitude of this reduction was mitigated in year 8: -8.5% ± 1.6% and in year 12: -10.3% ± 2.2% but all were significantly below the mean baseline value (p < 0.001). A similar pattern of decline was observed at the radius. Cortical porosity progressively increased at the tibia in year 5: 17.4% ± 10% (p < 0.05), year 8: 55.2% ± 11% (p < 0.001), and year 12: 83.5% ± 14% (p < 0.001). A similar pattern of increase was observed at the radius. Failure load, which was higher than normal at baseline, decreased but remained above normal at year 12. This is the longest experience, to date, with PTH therapy in HypoPT. These results demonstrate sustained biochemical stability but overall decreases in bone mass. © 2023 American Society for Bone and Mineral Research (ASBMR).

Vitamin D and malabsorptive gastrointestinal conditions: A bidirectional relationship?

This paper is one of the outcomes of the 5th International Conference "Controversies in Vitamin D" held in Stresa, Italy from 15 to 18 September 2021 as part of a series of annual meetings which was started in 2017. The scope of these meetings is to discuss controversial issues about vitamin D. Publication of the outcomes of the meeting in international journals allows a wide sharing of the most recent data with the medical and academic community. Vitamin D and malabsorptive gastrointestinal conditions was one of the topics discussed at the meeting and focus of this paper. Participants to the meeting were invited to review available literature on selected issues related to vitamin D and gastrointestinal system and to present their topic to all participants with the aim to initiate a discussion on the main outcomes of which are reported in this document. The presentations were focused on the possible bidirectional relationship between vitamin D and gastrointestinal malabsorptive conditions such as celiac disease, inflammatory bowel diseases (IBDs) and bariatric surgery. In fact, on one hand the impact of these conditions on vitamin D status was examined and on the other hand the possible role of hypovitaminosis D on pathophysiology and clinical course of these conditions was also evaluated. All examined malabsorptive conditions severely impair vitamin D status. Since vitamin D has known positive effects on bone this in turn may contribute to negative skeletal outcomes including reduced bone mineral density, and increased risk of fracture which may be mitigated by vitamin D supplementation. Due to the immune and metabolic extra-skeletal effects there is the possibility that low levels of vitamin D may negatively impact on the underlying gastrointestinal conditions worsening its clinical course or counteracting the effect of treatment. Therefore, vitamin D status assessment and supplementation should be routinely considered in all patients affected by these conditions. This concept is strengthened by the existence of a possible bidirectional relationship through which poor vitamin D status may negatively impact on clinical course of underlying disease. Sufficient elements are available to estimate the desired threshold vitamin D level above which a favourable impact on the skeleton in these conditions may be obtained. On the other hand, ad hoc controlled clinical trials are needed to better define this threshold for obtaining a positive effect of vitamin D supplementation on occurrence and clinical course of malabsorptive gastrointestinal diseases.

Vitamin D in the older population: a consensus statement.

BACKGROUND: This paper reports results from the 5th International Conference "Controversies in Vitamin D" that was held in Stresa, Italy, 15-18 September 2021. The conference is part of this series that started in 2017 and has been conducted annually since. The objective of these conferences is to identify timely and controversial topics related to Vitamin D. Dissemination of the results of the conference through publications in peer-reviewed journals is an important means by which the most up to date information can be shared with physicians, investigators, and other health care professionals. Vitamin D and aging, the subject of this paper was featured at the conference. METHODS: Participants were selected to review available literature on assigned topics related to vitamin D and aging and to present their findings with illustrative material, the intent of which was to stimulate discussion and to arrive at a consensus. The presentations were directed towards the following areas: impact of aging on vitamin D production and levels; skeletal effects of vitamin D deficiency in the older population; falls and vitamin D in the aging; potential extra skeletal effects of vitamin D; and strategies to prevent vitamin D deficiency. A final topic was related to how vitamin D might influence the efficacy of vaccines for Covid-19. RESULTS: Hypovitaminosis D can lead to several skeletal and extra-skeletal outcomes. Older adults are at risk for vitamin D deficiency as both production and metabolism of vitamin D change with aging due to factors, such as reduced sun exposure and reduced production capacity of the skin. Skeletal consequences of these age-related changes can include reduced bone mineral density, osteomalacia and fractures. Potential extra-skeletal effects can include added risks for falls, reduced muscle strength, diabetes, cancer, and cardiovascular disease. Strategies to avoid these vitamin D deficiency-related negative outcomes include sun exposure, food fortification, and supplementation. While aging does not diminish sufficient reserve capacity for cutaneous vitamin D production, concerns about skin cancers and practical matters for the institutionalized elderly limit this option. Supplementation with vitamin D is the best option either pharmacologically or through food fortification. Regardless of treatment strategies, interventions to restore sufficient vitamin D status will show positive results only in those who are truly deficient. Thus, treatment goals should focus on avoiding 25(OH)D serum levels <30 nmol/l, with a goal to reach levels >50 nmol/l. CONCLUSIONS: The results of this conference has led to consensus on several issues. Vitamin D supplementation should be combined with calcium to reduce fractures in the older population. The goal for adequate Vitamin D status should be to reach a serum level of 25(OH)D >50 nmol/l. It appears that daily low-dose vitamin D regimens reduce the risk of falling, especially in the elderly, compared with infrequent, large bolus doses that may increase it. The role of Vitamin D supplementation on muscle strength remains to be clarified. On the other hand, supplementation decreases the risk of progression to T2D from prediabetes among those who are Vitamin Ddeficient. Of three possible strategies to establish vitamin D sufficiency - sunshine exposure, food fortification, and supplementation - the latter seems to be the most effective and practical in the aging population.

Consensus and Controversial Aspects of Vitamin D and COVID-19.

OBJECTIVE: This work aims to review and discuss controversial topics in the field of vitamin D, SARS-CoV-2 infection, and COVID-19. METHODS: The International Conferences "Controversies in Vitamin D" are a series of workshops that started in 2017 featuring international experts and leaders in vitamin D research and clinical practice. The fifth annual conference was held in Stresa, Italy, September 15 to 18, 2021. EVIDENCE: Before the event, participants reviewed available studies on their assigned topic, drafted a related abstract, and presented their findings at the time of the conference. Relevant literature that became available since was also discussed within the panel and updated accordingly. CONSENSUS: Before the event, the drafted abstracts had been merged to prepare a preliminary document. After the conference presentations, in-depth discussions in open sessions led to consensus. The document was subsequently modified according to discussions and up-to-date literature inclusion. CONCLUSIONS: There is quite consistent evidence for an association between low 25 OH vitamin D (25(OH)D) levels and poor COVID-19 outcomes, despite heterogeneous publications of variable quality. However, the low vitamin D status in COVID-19 patients might also reflect reverse causality. Vitamin D supplementation might have a positive role in COVID-19 prevention. The evidence supporting a beneficial effect of vitamin D treatment in decreasing the risk of COVID-19 complications is conflicting. Conclusive statements regarding the beneficial effect of vitamin D in this context await high-quality, randomized controlled trials.

Parathyroid Hormone Therapy for Managing Chronic Hypoparathyroidism: A Systematic Review and Meta-Analysis.

The efficacy and safety of parathyroid hormone (PTH) therapy for managing long-term hypoparathyroidism is being evaluated in ongoing clinical trials. We undertook a systematic review and meta-analysis of currently available randomized controlled trials to investigate the benefits and harms of PTH therapy and conventional therapy in the management of patients with chronic hypoparathyroidism. To identify eligible studies, published in English, we searched Embase, PubMed, and Cochrane CENTRAL from inception to May 2022. Two reviewers independently extracted data and assessed the risk of bias. We defined patients' important outcomes and used grading of recommendations, assessment, development, and evaluation (GRADE) to provide the structure for quantifying absolute effects and rating the quality of evidence. Seven randomized trials of 12 publications that enrolled a total of 386 patients proved eligible. The follow-up duration ranged from 1 to 36 months. Compared with conventional therapy, PTH therapy probably achieves a small improvement in physical health-related quality of life (mean difference [MD] 3.4, 95% confidence interval [CI] 1.5-5.3, minimally important difference 3.0, moderate certainty). PTH therapy results in more patients reaching 50% or greater reduction in the dose of active vitamin D and calcium (relative risk [RR] = 6.5, 95% CI 2.5-16.4, 385 more per 1000 patients, high certainty). PTH therapy may increase hypercalcemia (RR =2.4, 95% CI 1.2-5.04, low certainty). The findings may support the use of PTH therapy in patients with chronic hypoparathyroidism. Because of limitations of short duration and small sample size, evidence from randomized trials is limited regarding important benefits of PTH therapy compared with conventional therapy. Establishing such benefits will require further studies. © 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).

Long-term consequences of osteoporosis therapy with denosumab.

Denosumab (DMAb) is a human monoclonal antibody used as an antiresorptive drug in the treatment of osteoporosis. Approval at a dosage of 60 mg every 6 months was based on the results of the randomized, placebo-controlled trial (FREEDOM). The design of this 3-year study included an extension for up to 10 years. Those who were randomized to DMAb continued on drug, while those who were randomized to placebo transitioned to DMAb. The 10-year experience with DMAb provides data on efficacy of drug in terms of reduced fractures and continued increases in bone mineral density (BMD). The 10-year experience with denosumab also provides information about rare complications associated with the use of DMAb, such as osteonecrosis of the jaw (ONJ), and atypical femoral fractures (AFF). This experience provided new insights into the reversibility of effects upon discontinuation without follow-on therapy with another agent. This review focuses upon prolonged treatment with DMAb, with regard to beneficial effects on fracture reduction and safety. Additionally, its use in patients with impaired renal function, compare its results with those of bisphosphonates (BPs), the occurrence/frequency of complications, in addition to the use of different tools, from imaging techniques to histological findings, to evaluate its effects on bone tissue.

Male osteoporosis.

Osteoporosis, a disease classically attributed to postmenopausal women, is underappreciated, underdiagnosed, and undertreated in men. However, it is not uncommon for osteoporotic fractures to occur in men. About 40% of fractures occur in men with an incidence that has increased over the years. After a first fracture, the risk of a subsequent episode, as well as the risk of death, is higher in the male than in the female population. Despite these facts, only 10% of men with osteoporosis receive adequate treatment. Up to half of the cases of male osteoporosis have a secondary cause, the most common being hypogonadism, excessive alcohol consumption, and chronic use of glucocorticoids. The International Society for Clinical Densitometry (ISCD) recommends using the female database for the diagnosis of osteoporosis by DXA (T-score ≤ -2.5 in men over 50 years old). In addition, osteoporosis can also be diagnosed independently of the BMD if a fragility fracture is present, or if there is a high risk of fractures by FRAX. Treatment is similar to postmenopausal osteoporosis, because the data regarding changes in bone density track closely to those in women. Data concerning fracture risk reduction are not as certain because the clinical trials have included fewer subjects for shorter period of time. In men with symptomatic hypogonadism, testosterone replacement, if indicated, can improve BMD.

Complications, Symptoms, Presurgical Predictors in Patients With Chronic Hypoparathyroidism: A Systematic Review.

The complications and symptoms of hypoparathyroidism remain incompletely defined. Measuring serum parathyroid hormone (PTH) and calcium levels early after total thyroidectomy may predict the development of chronic hypoparathyroidism. The study aimed (i) to identify symptoms and complications associated with chronic hypoparathyroidism and determine the prevalence of those symptoms and complications (Part I), and (ii) to examine the utility of early postoperative measurements of PTH and calcium in predicting chronic hypoparathyroidism (Part II). We searched Medline, Medline In-Process, EMBASE, and Cochrane CENTRAL to identify complications and symptoms associated with chronic hypoparathyroidism. We used two predefined criteria (at least three studies reported the complication and symptom and had statistically significantly greater pooled relative estimates). To estimate prevalence, we used the median and interquartile range (IQR) of the studies reporting complications and symptoms. For testing the predictive values of early postoperative measurements of PTH and calcium, we used a bivariate model to perform diagnostic test meta-analysis. In Part I, the 93 eligible studies enrolled a total of 18,973 patients and reported on 170 complications and symptoms. We identified nine most common complications or symptoms probably associated with chronic hypoparathyroidism. The complications or symptoms and the prevalence are as follows: nephrocalcinosis/nephrolithiasis (median prevalence among all studies 15%), renal insufficiency (12%), cataract (17%), seizures (11%), arrhythmia (7%), ischemic heart disease (7%), depression (9%), infection (11%), and all-cause mortality (6%). In Part II, 18 studies with 4325 patients proved eligible. For PTH measurement, regarding the posttest probability, PTH values above 10 pg/mL 12-24 hours postsurgery virtually exclude chronic hypoparathyroidism irrespective of pretest probability (100%). When PTH values are below 10 pg/mL, posttest probabilities range from 3% to 64%. Nine complications and symptoms are probably associated with chronic hypoparathyroidism. A PTH value above a threshold of 10 pg/mL 12-24 hours after total thyroidectomy is a strong predictor that the patients will not develop chronic hypoparathyroidism. Patients with PTH values below the threshold need careful monitoring as some will develop chronic hypoparathyroidism. © 2022 American Society for Bone and Mineral Research (ASBMR).

Proceedings of the 2022 Santa Fe Bone Symposium: Current Concepts in the Care of Patients with Osteoporosis and Metabolic Bone Diseases.

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones.