Objective: To investigating the relationship between α-Klotho and FGF-23 with bone biochemical markers and bone density findings in extremely aged individuals. Methods: A total of 55 individuals with a mean age of 85.6 years were subjected to clinical, biochemical, and bone mineral density analyses and the enzyme-linked immunosorbent assay-based detection of α-Klotho and FGF-23. The mean, standard deviation, median, and interquartile ranges of the sample values were determined, and Spearman's test for association assessments was used for statistical analysis. Results: The study participants expressed median FGF-23 and α-Klotho levels of 69.81 RU/mL (51.43 RU/mL) and 733.43 pg/mL (360.83 pg/mL), respectively. The majority of the participants possessed osteopenia (54.5%) and a vitamin D deficiency (57%). The 25-hydroxyvitamin D concentrations ranged between 7.1 and 47.5ng/mL, with a median of 18.1ng/mL. Conclusion: No substantial associations were discovered between α-Klotho and FGF-23 levels and bone density in the study participants. Objective αKlotho α Klotho FGF23 FGF 23 FGF-2 Methods 5 856 85 6 85. clinical enzymelinked enzyme linked assaybased assay based FGF23. 23. deviation determined Spearmans Spearman s analysis Results 6981 69 81 69.8 RUmL RU mL 51.43 5143 51 43 (51.4 73343 733 733.4 pgmL pg 360.83 36083 360 83 (360.8 pg/mL, , pg/mL) respectively 54.5% 545 54 (54.5% 57%. 57 57% . (57%) 25hydroxyvitamin hydroxyvitamin 25 71 7 1 7. 475ngmL ngmL 47 5ng ng 47.5ng/mL 181ngmL 18 1ng 18.1ng/mL Conclusion FGF2 2 FGF- 8 698 69. 51.4 514 4 (51. 7334 73 733. 360.8 3608 36 (360. 54.5 (54.5 (57% 51. (51 360. 3 (360 54. (54. (57 (5 (36 (54 ( (3

ABSTRACT 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.

ABSTRACT 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.

ABSTRACT Objective: The fibroblast growth factor 23 (FGF23) has been related to biological aging, but data in elderly individuals are scant. We determined the profile of serum FGF23 levels in a population of very-old individuals and studied their correlations with parameters of bone metabolism and health markers, as functional performance. Materials and methods: This cross-sectional study was performed on 182 community dwellers aged ≥ 80 years. Serum levels of FGF23, PTH, calcium, albumin, phosphorus, creatinine, bone markers, and bone mineral density data were analyzed. Physical performance was evaluated with the stationary march (Step), Flamingo, and functional reach tests, along with questionnaires to assess falls and fractures in the previous year, energy expenditure (MET), and the Charlson index (CI). Physical activity was evaluated with the International Physical Activity Questionnaire (IPAQ). Results: Most participants (75%) had FGF23 levels between 30-120 RU/mL (range: 6.0-3,170.0 RU/mL). FGF23 levels correlated with estimated glomerular filtration rate (eGFR; r = -0.335; p = 0.001) and PTH (r = 0.318; p < 0.0001). Individuals with FGF23 in the highest tertile had more falls in the previous year (p = 0.032), worse performance in the Flamingo (p = 0.009) and Step (p < 0.001) tests, worse CI (p = 0.009) and a trend toward sedentary lifestyle (p = 0.056). On multiple regression, FGF23 tertiles remained significant, independently of eGFR, for falls in the previous year, performance in the Flamingo and stationary march tests, lean mass index, and IPAQ classification. Conclusion: In a population of very elderly individuals, FGF23 levels were inversely associated with neuromuscular and functional performances. Higher concentrations were related to more falls, lower muscle strength and aerobic capacity, and poorer balance, regardless of renal function, suggesting a potentially deleterious role of high FGF23 concentrations in musculoskeletal health. Objective 2 FGF (FGF23 aging scant FGF2 veryold old markers methods crosssectional cross sectional 18 8 years calcium albumin phosphorus creatinine analyzed Step, , (Step) tests MET, MET (MET) CI. . (CI) IPAQ. (IPAQ) Results 75% 75 (75% 30120 30 120 30-12 RUmL RU mL range (range 6.03,170.0 6031700 6.0 3,170.0 6 0 3 170 6.0-3,170. RU/mL. RU/mL) eGFR (eGFR 0.335 0335 335 -0.335 0.001 0001 001 0.318 0318 318 0.0001. 00001 0.0001 0.0001) 0.032, 0032 0.032 032 0.032) 0.009 0009 009 0.056. 0056 0.056 056 0.056) regression significant classification Conclusion performances capacity balance function (FGF2 1 (Step (MET (CI (IPAQ 7 (75 3012 12 30-1 03 6.03,170. 603170 60 6. 31700 3,170. 17 6.0-3,170 0.33 033 33 -0.33 0.00 000 00 0.31 031 31 0000 0.000 003 0.03 005 0.05 05 (FGF (7 301 30- 6.03,170 60317 3170 3,170 6.0-3,17 0.3 -0.3 0.0 ( 6.03,17 6031 317 3,17 6.0-3,1 0. -0. 6.03,1 603 3,1 6.0-3, -0 6.03, 3, 6.0-3 - 6.03 6.0-

RESUMO Objetivo Examinar a associação entre o fator de crescimento de fibroblastos 23 sérico e a capacidade funcional em indivíduos independentes, com 80 anos ou mais. Métodos A capacidade funcional de 144 idosos foi avaliada por meio de Atividades Instrumentais da Vida Diária, testes cognitivos, força de preensão manual e capacidade de levantar de uma cadeira e sentar cinco vezes. O fator de crescimento de fibroblastos 23 foi medido pelo teste ELISA. Resultados Os participantes no tercil mais baixo de fator de crescimento de fibroblastos 23 tiveram a maior média±desvio-padrão da taxa de filtração glomerular estimada, concentração média de hemoglobina mais alta, menor número médio de doenças e menor número de medicamentos utilizados. Em participantes com taxa de filtração glomerular estimada >45mL/minuto/1,73m2, o nível médio do fator de crescimento de fibroblastos 23 foi maior naqueles com 25(OH) vitamina D <20ng/mL do que naqueles com 25(OH) vitamina D ≥20ng/mL (75,6RU/mL±42,8 versus 68,5RU/mL±41,7; p<0,001). Houve aumento na cistatina C sérica média (de 1,3mg/mL±0,3 a 1,5mg/mL±0,3 a 1,7mg/mL±0,4) em função do tercil de fator de crescimento 23 de fibroblastos mais alto (p<0,001). Os níveis de fator de crescimento de fibroblastos 23 não foram significativamente associados à capacidade em testes físicos ou cognitivos. Conclusão Em idosos independentes residentes na comunidade ≥80 anos, o fator de crescimento de fibroblastos 23 foi associado a comorbidades relacionadas à idade e à função renal, mas não à capacidade funcional.

ABSTRACT Objective To examine the association of between serum fibroblast growth factor 23 and the functional capacity among independent individuals, aged 80 or older. Methods The functional capacity of 144 elderly was assessed by Instrumental Activities of Daily Living, cognitive tests, handgrip strength and the timed ability to rise from a chair and sit down five times. Fibroblast growth factor 23 was measured using an ELISA assay. Results Participants in the lowest fibroblast growth factor 23 tertile had the highest mean±standard deviation estimated glomerular filtration rate, the highest mean hemoglobin level, the lowest average number of diseases and the lowest number of medications used. In participants with the estimated glomerular filtration rate >45mL/minute/1.73m2, mean fibroblast growth factor 23 level was higher in those with 25(OH) vitamin D <20ng/mL than in those with 25(OH) vitamin D ≥20ng/mL (75.6RU/mL±42.8 versus 68.5RU/mL±41.7; p<0.001). There was an increase in the mean serum cystatin C (from 1.3mg/mL±0.3 to 1.5mg/mL±0.3 to 1.7mg/mL±0.4) as function of higher fibroblast growth factor 23 tertile (p<0.001). Fibroblast growth factor 23 levels were not significantly associated with capacity in physical or cognitive tests. Conclusion In independent community-dwelling elderly, aged ≥80 years, fibroblast growth factor 23 was associated with aged-related comorbidities and renal function but not with functional capacity.

ABSTRACT Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture leading to an increased risk of fractures. Fragility fractures, especially hip fractures, are associated with a significant reduction in the physical function and quality of life of affected patients, as well as increased mortality, leading to a major financial impact on health care. Many drugs have been registered for the treatment of osteoporosis and very recently, a new anabolic agent, romosozumab, has been approved in some countries. Despite the expansion of efficacious antiresorptive and anabolic therapies in recent years, a concomitant increase in concerns have been raised by physicians, patients and the lay press about the potential for adverse events, especially atypical femoral fractures (AFF) following prolonged use of bisphosphonates. Whatever the mechanism(s) may be, direct or indirect, linking prolonged bisphosphonate use to atypical femoral fractures, this adverse event is very rare in comparison to the magnitude of risk reduction of typical osteoporotic fractures. An estimated 162 osteoporosis-related fractures are prevented for each atypical femoral fracture associated with an anti-resorptive medication. Until a risk calculator for predicting risk of atypical fractures, becomes available in clinical practice, and we view this as an unlikely scenario, it is up to the physician to consider continuing or discontinuing bisphosphonate use after the critical 3-5 year period of treatment with zoledronic acid or alendronate, but close monitoring for the residual bone effects overtime should be planned. For other bisphosphonates, in which no residual effects are expected, drug holiday is usually not applied.

ABSTRACT Objective Vertebral fracture is the most common osteoporotic fracture, affecting quality of life and increasing mortality. Epidemiological data on incidence of vertebral fracture are scarce in Brazil and throughout Latin America. Our aim was to determine vertebral fracture incidence and risk factors in a female Brazilian population. Subjects and methods Postmenopausal women with low bone mass were studied from the Brazilian placebo group of Arzoxifene Generations Trial (n = 974), followed for up to 5 years. The primary endpoint was new vertebral fractures, detected by X-Ray. Experimental design defined two strata: A. Osteoporosis or previous vertebral fracture with osteopenia; B. Osteopenia without previous fracture. Previous fracture, T-score, ionized calcium, alkaline phosphatase, creatinine and glucose were analyzed at baseline. Crude and adjusted incidence rates of vertebral fractures were estimated and Poisson regression model was used. Results Incidence rate was 7.7 (95% CI of 5.4 to 10.9) per 1,000 person-years (PY), increasing as a function of age. Women with new vertebral fractures had higher prevalence of previous nonvertebral fracture after menopause, were older and had lower lumbar spine (LS) T-score. Fracture risk increased by 46% for each unit reduction in LS T-score. Variables correlated with new vertebral fracture were age (p = 0.034), LS T-score, stratum A (p = 0.001 for both) and previous nonvertebral fracture after menopause (p = 0.019). In the final model, LS T-score was the strongest predictor. Conclusions Incidence rate of vertebral fracture of 7.7 per 1,000 PY. Age and previous fractures were associated with new vertebral fracture, but LS T-score was the most important predictor.

TBS (do inglês, “trabecular bone score”) é um novo método que estima a microarquitetura óssea a partir de uma imagem de densitometria óssea (DXA) da coluna lombar. Apesar de o TBS não ser uma medida física direta da microarquitetura trabecular, ele correlaciona-se com o volume ósseo, densidade da conectividade trabecular, número de trabéculas e separação trabecular medidos por microtomografia computadorizada (µCT), e com medidas mecânicas da resistência óssea vertebral em estudos ex vivo. Estudos em humanos confirmaram que o TBS associa-se a microarquitetura trabecular e resistência óssea medidas por tomografia computadorizada quantitativa periférica de alta resolução (HRpQCT). Estudos transversais e prospectivos, envolvendo um grande número de indivíduos, mostraram que o TBS é associado com fratura vertebral, de colo de fêmur e com outros tipos de fraturas osteoporóticas em mulheres na pós-menopausa. Dados em homens, apesar de escassos, mostram resultados semelhantes. Além disso, o TBS foi associado a fraturas por fragilidade em indivíduos com diversas causas secundárias de osteoporose e, dados preliminares, sugerem que o uso do TBS pode melhorar a previsão de fratura quando incorporado ao sistema de avaliação de risco de fratura (FRAX). Este artigo faz uma revisão de avanços recentes que têm ajudado a estabelecer esse novo método de imagem.

The trabecular bone score (TBS) is a new method to describe skeletal microarchitecture from the dual energy X-ray absorptiometry (DXA) image of the lumbar spine. While TBS is not a direct physical measurement of trabecular microarchitecture, it correlates with micro-computed tomography (µCT) measures of bone volume fraction, connectivity density, trabecular number, and trabecular separation, and with vertebral mechanical behavior in ex vivo studies. In human subjects, TBS has been shown to be associated with trabecular microarchitecture and bone strength by high resolution peripheral quantitative computed tomography (HRpQCT). Cross-sectional and prospective studies, involving a large number of subjects, have both shown that TBS is associated with vertebral, femoral neck, and other types of osteoporotic fractures in postmenopausal women. Data in men, while much less extensive, show similar findings. TBS is also associated with fragility fractures in subjects with secondary causes of osteoporosis, and preliminary data suggest that TBS might improve fracture prediction when incorporated in the fracture risk assessment system known as FRAX. In this article, we review recent advances that have helped to establish this new imaging technology.

A doença óssea no hiperparatiroidismo primário grave é representada pela osteíte fibrosa cística (OFC). Dor óssea, deformidades esqueléticas e fraturas patológicas são achados comuns na OFC. A densidade mineral óssea está, usualmente, extremamente diminuída na OFC, mas é reversível após a cura cirúrgica. Os sinais e sintomas da doença óssea grave incluem dor óssea, fraturas patológicas e fraqueza muscular proximal com hiper-reflexia. O comprometimento ósseo é tipicamente caracterizado pela aparência em “sal-e-pimenta” nos ossos do crânio, erosões ósseas e reabsorção das falanges, tumores marrons e cistos. Na radiografia, observam-se desmineralização difusa e fraturas patológicas especialmente nos ossos longos das extremidades. No hiperparatiroidismo primário (HPTP) sintomático grave, as concentrações séricas de cálcio e PTH estão usualmente bem elevadas e o comprometimento renal se caracteriza pela presença de urolitíase e nefrocalcinose. Uma nova tecnologia, recentemente aprovada para uso clínico nos Estados Unidos e na Europa, torna-se provável se difundir rapidamente, pois utiliza as imagens geradas pela densitometria DXA. O escore trabecular ósseo (TBS), obtido por meio da análise do nível da textura cinza das imagens dos corpos vertebrais, fornece informações indiretas sobre a microarquitetura trabecular. Novos métodos, como a tomografia de alta resolução quantitativa periférica computadorizada (HRpqCT), têm proporcionado conhecimentos adicionais sobre os achados da microarquitetura esquelética no HPTP.

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.

Diversos fatores estão envolvidos na determinação da qualidade óssea, incluindo a densidade óssea, a remodelação óssea, a extensão da conectividade do osso trabecular, porosidade cortical e geometria. Metabolicamente ativo e, em um processo contínuo de remodelação, cerca de 20% do tecido ósseo é renovado anualmente. Por sua vez, marcadores de turnover ósseo (BTM) são frequentemente utilizados em estudos clínicos e fornecem informações válidas sobre a eficácia do tratamento da osteoporose, o que reflete o metabolismo ósseo e sua resposta ao tratamento, embora eles não sejam úteis somente para estimar a perda óssea. Nesta revisão, o comportamento dos BTM em ensaios clínicos diferentes e com diferentes drogas osteoporóticas será abordado.

Several factors are involved in determining bone quality including bone density, bone turnover, the extent of trabecular bone connectivity, cortical porosity and geometry. Metabolically active and in a continuous process of remodeling, approximately 20% of bone tissue is renewed annually. Bone turn over markers (BTM) are frequently used in clinical trials and to provide valid information about the effectiveness of osteoporosis treatment, reflecting the state of bone metabolism and its response to treatment, although they are not useful alone to estimate bone loss. In this review the behavior of BTM from different clinical trials or different osteoporotic drugs will be addressed.

A consolidação adequada da fratura osteoporótica é essencial para recuperação funcional, morbidade e qualidade de vida. Alguns tratamentos para osteoporose podem afetar os processos associados ao reparo ósseo. Por exemplo, os bisfosfonatos, em modelos experimentais, estão associados com aumento do tamanho do calo e a mineralização, reduzindo o remodelamento do calo e melhorando a força mecânica. Tratamento com bisfosfonato, local ou sistêmico, pode melhorar a fixação de implantes. Não foi observado impacto negativo na consolidação da fratura, mesmo após uma cirurgia maior ou quando administrado imediatamente após a fratura. Relatos e um estudo randomizado com o osteoanabólico teriparatida produziram resultados mistos, mas que são consistentes com o impacto positivo da teriparatida na consolidação da fratura. Algumas das drogas que estão sendo desenvolvidas no momento para osteoporose, como anticorpos para esclerotina e DKK1, têm mostrado efeito benéfico na consolidação da fratura. No estágio atual, portanto, não há evidência de que terapias para osteoporose impeçam a consolidação da fratura, mas existem algumas evidências experimentais promissoras de efeito positivo na consolidação, especialmente daqueles agentes cuja ação é primariamente anabólica.

Satisfactory healing of the osteoporotic fracture is critically important to functional recovery, morbidity, and quality of life. Some therapies for osteoporosis may affect the processes associated with bone repair. For example, bisphosphonates in experimental models are associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. For the osteoanabolic agent teriparatide, case reports and a randomized trial have produced mixed results, but they are consistent with a positive impact of teriparatide on fracture healing. Some of the agents currently being developed for osteoporosis, notably sclerostin and DKK1 antibodies have shown a beneficial effect on fracture healing. At this point, therefore, there is no evidence that osteoporosis therapies are detrimental to fracture healing with some promising experimental evidence for positive effects on healing, notably for those agents whose actions are primarily anabolic.

OBJETIVO: O hipoparatiroidismo é uma doença em que há diminuição dos níveis circulantes do paratormônio, em geral, causada por destruição autoimune ou exerese cirúrgica. O objetivo deste estudo foi descrever as anormalidades microestrutrurais esqueléticas, como também o potencial terapêutico do uso do PTH(1-84). SUJEITOS E MÉTODOS: Histomorfometria padrão e análise de micro-CT foram realizadas em biópsias de crista ilíaca de indivíduos com hipoparatiroidismo. Os participantes foram tratados com PTH(1-84) por dois anos. RESULTADOS: A densidade óssea aumentou e os achados esqueléticos refletiram o estado de baixa remodelação óssea com maior BV/TV, Tb Wi e CT Wi, como também supressão de MS e BFR/BS quando comparado com o grupo controle. Com o uso de PTH(1-84), a remodelação óssea aumentou e a densidade óssea aumentou na coluna lombar. As necessidades de cálcio e vitamina D diminuíram e a calciúria não mudou. CONCLUSÃO: A microestrutura esquelética anormal no hipoparatiroidismo reflete a ausência do PTH. A terapia de reposição com PTH tem o potencial de reverter essas anormalidades, como também reduzir as necessidades de cálcio e vitamina D.

OBJECTIVE: Hypoparathyroidism is a disorder in which parathyroid hormone is deficient in the circulation due most often to immunological destruction of the parathyroids or to their surgical removal. The objective of this work was to define the abnormalities in skeletal microstructure as well as to establish the potential efficacy of PTH(1-84) replacement in this disorder. SUBJECTS AND METHODS: Standard histomorphometric and µCT analyses were performed on iliac crest bone biopsies obtained from patients with hypoparathyroidism. Participants were treated with PTH(1-84) for two years. RESULTS: Bone density was increased and skeletal features reflected the low turnover state with greater BV/TV, Tb. Wi and Ct. Wi as well as suppressed MS and BFR/BS as compared to controls. With PTH(1-84), bone turnover and bone mineral density increased in the lumbar spine. Requirements for calcium and vitamin D fell while serum and urinary calcium concentrations did not change. CONCLUSION: Abnormal microstructure of the skeleton in hypoparathyroidism reflects the absence of PTH. Replacement therapy with PTH has the potential to correct these abnormalities as well as to reduce the requirements for calcium and vitamin D.

O hiperparatiroidismo primário (HPTP) é uma doença comum caracterizada por uma regulação inadequada da secreção do paratormônio em uma ou mais glândulas paratiroides. Historicamente a doença pode ser dividida em duas eras. Quando o HPTP foi descoberto há 80 anos, era sempre sintomático com nefrolitíase, doença óssea e acentuada hipercalcemia. Com o advento das rotinas laboratoriais por autoanalisadores bioquímicos há 40 anos, o fenótipo clínico mudou para uma doença sintomaticamente leve na ausência daqueles achados clássicos. Está se entrando numa terceira era em que os pacientes são diagnosticados com calcemia normal na presença de níveis circulantes elevados do paratormônio. Neste artigo, descreve-se essa nova entidade, hiperparatiroidismo primário normocalcêmico, uma forma frusta da doença.

Primary hyperparathyroidism is a common disorder of mineral metabolism characterized by incompletely regulated, excessive secretion of parathyroid hormone from one or more of the parathyroid glands. The historical view of this disease describes two distinct entities marked by two eras. When primary hyperparathyroidism was first discovered about 80 years ago, it was always symptomatic with kidney stones, bone disease and marked hypercalcemia. With the advent of the multichannel autoanalyzer about 40 years ago, the clinical phenotype changed to a disorder characterized by mild hypercalcemia and the absence of classical other features of the disease. We may now be entering a 3rd era in the history of this disease in which patients are being discovered with normal total and ionized serum calcium concentrations but with parathyroid hormone levels that are consistently elevated. In this article, we describe this new entity, normocalcemic primary hyperparathyroidism, a forme fruste of the disease.