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The use of glucocorticoids in the treatment of medical disorders can lead to rapid bone loss and increased risk of fragility fracture. Updated clinical guidelines are needed that accommodate recent advances in fracture risk assessment and new pharmacological interventions to reduce fracture risk. This document serves as an appendix to the 2012 IOF-ECTS guidelines for the management of glucocorticoid-induced osteoporosis.

Osteoporotic fractures and adverse skeletal effects of malignancies are associated with high bone turnover. Denosumab is a potent inhibitor of bone resorption with a novel mechanism of action. It is administered as an infrequent subcutaneous injection with no restrictions relating to renal function. This review summarizes data on the efficacy and safety of denosumab that led to its approval for the treatment of postmenopausal osteoporosis, cancer treatment-induced bone loss, and skeletal complications of malignancies.

PTH, an 84-amino acid peptide hormone synthesized by the parathyroid glands, is essential for the maintenance of calcium homeostasis.While in its traditional metabolic role, PTH helps to maintain the serum calcium concentration within narrow, normal limits and participates as a determinant of bone remodeling, more specific actions, described as catabolic and anabolic are also well known. Clinically, the catabolic effect of PTH is best represented by primary hyperparathyroidism (PHPT), while the osteoanabolic effect of PTH is best seen when PTH or its biological amino-terminal fragment [PTH(1-34)] is used as a therapy for osteoporosis. These dual functions of PTH are unmasked under very specific pathological (PHPT) or therapeutic conditions. At the cellular level, PTH favors bone resorption, mostly by affecting the receptor activator of nuclear factor κ-B (RANK) ligand (RANKL)-osteoprotegerin- RANK system, leading to an increase in osteoclast formation and activity. Increased bone formation due to PTH therapy is explained best by its ability to enhance osteoblastogenesis and/or osteoblast survival. The PTH-induced bone formation is mediated, in part, by a decrease in SOST/sclerostin expression in osteocytes. This review focuses on the dual anabolic and catabolic actions of PTH on bone, situations where one is enhanced over the other, and the cellular and molecular mechanisms by which these actions are mediated.

Unlabelled: The consensus views on osteoporosis in men are reported., Introduction: A workshop was convened within a meeting on osteoporosis in men to identify areas of consensus amongst the panel (the authors) and the participants of the meeting., Methods: A public debate with an expert panel on preselected topics was conducted., Results and Conclusions: Consensus views were reached on diagnostic criteria and several aspects on the pathophysiology and treatment of osteoporosis in men.

Unlabelled: The introduction of the WHO FRAX® algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware and are the focus of this review, Introduction: The International Osteoporosis Foundation (IOF) and the International Society for Clinical Densitometry (ISCD) appointed a joint Task Force to develop resource documents in order to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met in November 2010 for 3 days to discuss these topics which form the focus of this review., Methods: This study reviews the resource documents and joint position statements of ISCD and IOF., Results: Details on the clinical risk factors currently used in FRAX are provided, and the reasons for the exclusion of others are provided. Recommendations are made for the development of surrogate models where country-specific FRAX models are not available., Conclusions: The wish list of clinicians for the modulation of FRAX is large, but in many instances, these wishes cannot presently be fulfilled; however, an explanation and understanding of the reasons may be helpful in translating the information provided by FRAX into clinical practice.

Context: Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations., Objective: The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity., Design and Setting: The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT., Patients: Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15)., Intervention: The intervention in this study was treatment with cinacalcet for up to 4.5 yr., Outcomes: Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period., Results: The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories., Conclusions: Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.

Context: The osteoanabolic properties of PTH may be due to increases in the number and maturity of circulating osteogenic cells. Hypoparathyroidism is a useful clinical model because this hypothesis can be tested by administering PTH., Objective: The objective of the study was to characterize circulating osteogenic cells in hypoparathyroid subjects during 12 months of PTH (1-84) administration., Design: Osteogenic cells were characterized using flow cytometry and antibodies against osteocalcin, an osteoblast-specific protein product, and stem cell markers CD34 and CD146. Changes in bone formation from biochemical markers and quadruple-labeled transiliac crest bone biopsies (0 and 3 month time points) were correlated with measurements of circulating osteogenic cells., Setting: The study was conducted at a clinical research center., Patients: Nineteen control and 19 hypoparathyroid patients were included in the study., Intervention: Intervention included the administration of PTH (1-84)., Results: Osteocalcin-positive cells were lower in hypoparathyroid subjects than controls (0.7 ± 0.1 vs. 2.0 ± 0.1%; P < 0.0001), with greater coexpression of the early cell markers CD34 and CD146 among the osteocalcin-positive cells in the hypoparathyroid subjects (11.0 ± 1.0 vs. 5.6 ± 0.7%; P < 0.001). With PTH (1-84) administration, the number of osteogenic cells increased 3-fold (P < 0.0001), whereas the coexpression of the early cell markers CD34 and CD146 decreased. Increases in osteogenic cells correlated with circulating and histomorphometric indices of osteoblast function: N-terminal propeptide of type I procollagen (R(2) = 0.4, P ≤ 0.001), bone-specific alkaline phosphatase (R(2) = 0.3, P < 0.001), osteocalcin (R(2) = 0.4, P < 0.001), mineralized perimeter (R(2) = 0.5, P < 0.001), mineral apposition rate (R(2) = 0.4, P = 0.003), and bone formation rate (R(2) = 0.5, P < 0.001)., Conclusions: It is likely that PTH stimulates bone formation by stimulating osteoblast development and maturation. Correlations between circulating osteogenic cells and histomorphometric indices of bone formation establish that osteoblast activity is being identified by this methodology.

Unlabelled: Hypoparathyroidism, a disorder characterized by low parathyroid hormone (PTH), is generally treated with oral calcium and vitamin D supplementation. We investigated the effects of PTH(1-84) treatment in 30 hypoparathyroid subjects for 24 months. PTH(1-84) treatment in hypoparathyroidism significantly reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels., Introduction: Hypoparathyroidism, a disorder characterized by low PTH, is associated with hypocalcemia, hypercalciuria, and increased bone mineral density (BMD). Conventional therapy with calcium and 1,25-dihydroxyvitamin D can maintain the serum calcium concentration, but doses are high, and control is variable. We investigated the effects of human PTH(1-84) treatment in hypoparathyroidism., Methods: Thirty subjects with hypoparathyroidism were treated in an open-label study of PTH(1-84) 100 µg every other day by subcutaneous injection for 24 months, with monitoring of calcium and vitamin D supplementation requirements, serum and 24 h urinary calcium excretion, and BMD by dual energy X-ray absorptiometry., Results: Requirements for supplemental calcium decreased significantly (3,030±2,325 to 1,661±1,267 mg/day (mean±SD); p<0.05), as did requirements for supplemental 1,25-dihydroxyvitamin D (0.68±0.5 to 0.40±0.5 µg/day; p<0.05). Serum calcium levels and 24 h urinary calcium excretion were mostly unchanged at 24 months. BMD increased at the lumbar spine by 2.9±4% from baseline (p<0.05), while femoral neck BMD remained unchanged and distal one third radial BMD decreased by 2.4±4% (p<0.05)., Conclusion: PTH(1-84) treatment in hypoparathyroidism significantly reduces supplemental calcium and 1,25-dihydroxyvitamin D requirements without generally altering serum and urinary calcium levels.

Low trauma fractures are the cardinal manifestation of osteoporosis. Their occurrence supersedes bone mineral density in deciding whether specific therapy is warranted. We therefore disagree with the notion that a densitometric threshold for treatment should be applied to patients over age 50 who suffer low trauma distal radius fracture.

Summary: Using national discharge and medical claims data, we studied the epidemiology of femoral fractures from 1996 to 2006. The annual hip fracture incidence declined from 600/100,000 to 400/100,000, without decline in the more rare femur fractures. Incidence rates for subtrochanteric and femoral shaft fractures were each below 20 per 100,000., Introduction: This study's purpose is to describe the site-specific epidemiology of femur fractures among people aged 50 and older., Methods: Using the National Hospital Discharge Survey from 1996 to 2006 and a large medical claims database (MarketScan), we studied epidemiology of all femur fractures. Hip fractures were grouped together; subtrochanteric, shaft, and distal femur fractures were kept separate., Results: In females, the overall hospital discharge rates of hip fracture decreased from about 600/100,00 to 400/100,000 person-years from 1996 to 2006. Subtrochanteric, femoral shaft, and lower femur rates remained stable, each approximately 20 per 100,000 person-years. Similar trends but lower rates existed in males. No significant trends were found in any of these fractures during the more recent years of 2002-2006 (MarketScan data). Using MarketScan, the overall incidence of hip fracture was <300/100,000 person-years; incidence of subtrochanteric and femoral shaft fractures combined was <25/100,000 person-years and distal femur fracture incidence was <18/100,000 person-years in females; rates were lower in males. The incidence of hip and other femur fractures increased exponentially with age., Conclusions: We found no evidence of an increasing incidence of any femoral fracture. Hip fracture incidence is declining but the incidence of each of the more rare femur fractures (distal to the lesser trochanter) is stable over time.

Unlabelled: We compared microarchitecture and mechanical competence parameters measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element analysis of radius and tibia to those measured by histomorphometry, micro-CT, and finite-element analysis of transiliac bone biopsies. Correlations were weak to moderate between parameters measured on biopsies and scans., Introduction: HR-pQCT is a new imaging technique that assesses trabecular and cortical bone microarchitecture of the radius and tibia in vivo. The purpose of this study was to determine the extent to which microarchitectural variables measured by HR-pQCT reflect those measured by the "gold standard," transiliac bone biopsy., Methods: HR-pQCT scans (Xtreme CT, Scanco Medical AG) and iliac crest bone biopsies were performed in 54 subjects (aged 39 +/- 10 years). Biopsies were analyzed by 2D quantitative histomorphometry and 3D microcomputed tomography (microCT). Apparent Young's modulus, an estimate of mechanical competence or strength, was determined by micro-finite-element analysis (microFE) of biopsy microCT and HR-pQCT images., Results: The strongest correlations observed were between trabecular parameters (bone volume fraction, number, separation) measured by microCT of biopsies and HR-pQCT of the radius (R 0.365-0.522; P < 0.01). Cortical width of biopsies correlated with cortical thickness by HR-pQCT, but only at the tibia (R = 0.360, P < 0.01). Apparent Young's modulus calculated by microFE of biopsies correlated with that calculated for both radius (R = 0.442; P < 0.001) and tibia (R = 0.380; P < 0.001) HR-pQCT scans., Conclusions: The associations between peripheral (HR-pQCT) and axial (transiliac biopsy) measures of microarchitecture and estimated mechanical competence are significant but modest.

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. Bisphosphonates are considered the first-line treatment option for the majority of glucocorticoid-treated patients at increased risk of fractures. However, the anti-resorptive mechanism of bisphosphonates does not address the major pathophysiological mechanisms of impaired bone formation during chronic glucocorticoid treatment. PTH, when administered intermittently and at low doses, has effects on bone formation opposite to those of glucocorticoids and therefore is conceptually a more attractive approach. Teriparatide (1-34PTH) has been studied in patients with GIO with effects on bone mineral density and on fracture risk which were shown to be superior to those obtained with alendronate.

Context: Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia., Objective: The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT., Design: This was an open-label, single-arm study comprising a titration phase of variable duration (2-16 wk) and a maintenance phase of up to 136 wk., Setting: The study was conducted at 23 centers in Europe, the United States, and Canada., Patients: The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter)., Intervention: During the titration phase, cinacalcet dosages were titrated every 2 wk (30 mg twice daily to 90 mg four times daily) for 16 wk until serum calcium was 10 mg/dl or less (2.5 mmol/liter). If serum calcium increased during the maintenance phase, additional increases in the cinacalcet dose were permitted., Main Outcome Measure: The primary end point was the proportion of patients experiencing a reduction in serum calcium of 1 mg/dl or greater (0.25 mmol/liter) at the end of the titration phase., Results: Mean +/- sd baseline serum calcium was 12.7 +/- 0.8 mg/dl (3.2 +/- 0.2 mmol/liter). At the end of titration, a 1 mg/dl or greater reduction in serum calcium was achieved in 15 patients (88%). Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. The most common adverse events were nausea, vomiting, and paresthesias., Conclusions: In patients with intractable PHPT, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.

The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

HRPT2 and parafibromin studies improved the diagnostic accuracy in two patients with primary hyperparathyroidism (PHPT) referred to us after surgery, in whom the clinical data were at variance with the pathological diagnosis of adenoma and carcinoma, respectively. Patients were referred to us after parathyroidectomy. Patient #1 had had a 1.5-cm tumor easily removed with a histological diagnosis of parathyroid carcinoma and normocalcemia for 2 years. Re-examination of the histology showed no cardinal signs of parathyroid cancer. Patient #2, with severe PHPT, had had the removal of a 3.5-cm tumor described histologically as adenoma. Ten years later PHPT recurred and persisted despite removal of two mildly enlarged parathyroid glands that were histologically normal. Re-review of the initial histology showed a trabecular pattern, fibrous bands, and atypical mitoses, suggesting an atypical adenoma. Because of the suspicion that case #1 could be an atypical adenoma and case #2 a carcinoma further molecular studies were performed. No HRPT2 and parafibromin abnormalities were identified in patient #1, strongly indicating a benign lesion. In patient #2, an HRPT2 germline mutation was found (E115X in exon 4) and associated with no parafibromin staining. These data, together with the clinical features, supported the suspicion of a parathyroid carcinoma that was confirmed by histological examination of further slides of the tumor, showing capsular and vascular invasion. A lung 1.5-cm nodule detected by computed tomography was excised. Histology showed a metastasis of parathyroid carcinoma. HRPT2 gene studies improved the diagnostic accuracy in 2 parathyroid tumors that are of uncertain type.

Background: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain., Methods: In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels., Results: During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups., Conclusions: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.), (2008 Massachusetts Medical Society)

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis with fractures occurring in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Calcium and vitamin D are important measures in the primary prevention of GIO. However, vitamin D and calcium alone do not allow to prevent fractures. Estrogens and androgens should be used in patients with documented hypogonadism. Bisphosphonates are the most effective of the various therapies that have been assessed for the management of GIO. These drugs need to be started early in order to correct the increase in bone resorption occurring in the first weeks of glucocorticoid treatment. Anabolic therapeutic strategies are under investigation. Teriparatide seems to be also efficacious for the treatment of patients with GIO.

Calcimimetics reduce serum levels of parathyroid hormone (PTH) and calcium, with a leftward shift in the set-point for calcium-regulated PTH secretion. The aim of this publication is to review the data available for calcimimetics in primary, secondary and tertiary hyperparathyroidism (HPT). Parathyroidectomy (PTX) is currently the only curative treatment for primary HPT, and recommended for patients with moderate-to-severe disease, as defined by a 2002 National Institute's of Health summary statement. In general, patients with primary HPT not meeting these surgical criteria, as well as those with contraindication or refusal for surgery, are monitored for signs and symptoms of primary HPT. There are currently no non-surgical therapies approved for use in primary HPT, although bisphosphonates are used in some patients, in an effort to control serum calcium levels. Calcimimetics decrease PTH and calcium levels and are a potential alternative for patients contraindicated for PTX, or who have failed previous PTX and have recurrent primary HPT. Secondary HPT develops early in chronic kidney disease and is present virtually in all patients with end-stage renal disease (ESRD). Secondary HPT is a progressive disease and is associated with several systemic complications, including renal osteodystrophy, soft tissue and vascular calcifications, and adverse cardiovascular outcomes. In ESRD patients, calcimimetics were shown to simultaneously reduce PTH, calcium, phosphate and calcium x phosphate product. In addition, observational analyses of use of calcimimetics in the ESRD population have shown a reduction of important clinical outcomes. In renal allograft recipients with tertiary HPT and hypercalcaemia, calcimimetics are a promising treatment option to control the parameters of calcium phosphate metabolism and may be a valid alternative to PTX. Based on its unique mechanism of action, the calcimimetic cinacalcet may play a role in the medical treatment of primary and tertiary forms of HPT, in addition to the registered indication for the treatment of secondary HPT.

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. Fractures, which are often asymptomatic, may occur in as many as 30-50% of patients receiving chronic glucocorticoid therapy. Vertebral fractures occur early after exposure to glucocorticoids, at a time when bone mineral density (BMD) declines rapidly. Fractures tend to occur at higher BMD levels than in women with postmenopausal osteoporosis. In human subjects, the early rapid decline in BMD is followed by a slower progressive decline in BMD. Glucocorticoids have direct and indirect effects on the skeleton. The primary effects are on osteoblasts and osteocytes. Glucocorticoids impair the replication, differentiation and function of osteoblasts and induce the apoptosis of mature osteoblasts and osteocytes. These effects lead to a suppression of bone formation, a central feature in the pathogenesis of GIO. Glucocorticoids also favor osteoclastogenesis and as a consequence increase bone resorption. Bisphosphonates are effective in the prevention and treatment of GIO. Anabolic therapeutic strategies are under investigation.

Background: Management of inoperable parathyroid carcinoma presents a challenge because until recently, effective medical therapy was not available. Morbidity and mortality result primarily from severe hypercalcemia. We assessed the ability of the calcimimetic cinacalcet HCl to reduce serum calcium in patients with parathyroid carcinoma as well as its effect on PTH concentrations, bone turnover markers, safety, and health-related quality of life variables., Methods: Twenty-nine patients with parathyroid carcinoma were enrolled in this open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated (30 mg twice daily to 90 mg four times daily) for 16 wk or until serum calcium was no more than 10.0 mg/dl. The study endpoint was the proportion of patients with at least a 1 mg/dl reduction in serum calcium at the end of the titration phase (responders)., Results: Mean (+/- se) serum calcium (14.1 +/- 0.4 mg/dl) and PTH (697 +/- 94 pg/ml) were markedly elevated at baseline. At the end of the titration period, serum calcium was reduced by at least 1 mg/dl in 62% of patients (mean decline to 12.4 +/- 0.5 mg/dl). In the 18 responders, serum calcium fell from 15.0 +/- 0.5 to 11.2 +/- 0.3 mg/dl (P < 0.001). The greatest reductions in serum calcium were observed in patients with highest baseline calcium levels. PTH levels decreased, but not significantly, to 635 +/- 73 pg/ml (-4.6%). Adverse events included nausea, vomiting, headache, and fracture., Conclusions: Cinacalcet effectively reduces hypercalcemia in approximately two thirds of patients with inoperable parathyroid carcinoma and may represent an important new treatment option for these patients.

Context: Patients with elevated PTH and consistently normal serum calcium levels, in whom secondary causes of hyperparathyroidism have been excluded, may represent the earliest presentation of primary hyperparathyroidism (PHPT)., Objective: The objective of the study was to characterize patients with normocalcemic PHPT referred to a bone disease unit., Design: This was a longitudinal cohort study., Setting: Ambulatory patients were referred to the metabolic bone disease unit., Patients: The study population included 37 patients [aged 58 yr, range 32-78; 95% female; serum calcium, 9.4 +/- 0.1 (sem) mg/dl (2.3 +/- 0.02 mmol/liter), reference range, 8.5-10.4 (2.1-2.6 mmol/liter); PTH, 93 +/- 5 pg/ml]., Interventions: Interventions included yearly (median 3 yr; range 1-8 yr) physical examination, biochemical indices, and bone mineral density (BMD)., Main Outcome Measures: We measured the development of features of PHPT., Results: Evaluation for classical features of PHPT revealed a history of kidney stones in five (14%), fragility fractures in four (11%), and osteoporosis in 57% [spine (34%), hip (38%), and/or distal one third radius (28%)]. BMD did not show preferential bone loss at the distal one third radius (T scores: spine, -2.00 +/- 0.25; hip, -1.84 +/- 0.18; one third radius, -1.74 +/- 0.22). Further signs of PHPT developed in 40% (seven hypercalcemia; one kidney stone; one fracture; two marked hypercalciuria; six had >10% BMD loss at one or more site(s) including four patients developing World Health Organization criteria for osteoporosis). Seven patients (three hypercalcemic, four persistently normocalcemic) underwent successful parathyroidectomy., Conclusions: Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT and develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT.

Unlabelled: In the PaTH trial, among the 119 women randomized to parathyroid hormone PTH(1-84) and 60 to alendronate, we found much greater variation in BMD and markers in response to PTH(1-84) compared to alendronate. No baseline participant characteristic consistently predicted increased bone density response to PTH(1-84), although women with larger changes in 1,25 dihydroxyvitamin D during therapy had larger increases in BMD., Introduction: We examined variability in BMD and markers of bone turnover in response to treatment with PTH(1-84) or alendronate in the PaTH trial., Methods: Differences in SD were examined using Levine's test for homogeneity of variance. Change in BMD across quartiles of participant characteristics was examined using ANOVA., Results: We found much greater variation in response to PTH(1-84) compared to alendronate. The SD for change in cancellous spine BMD (by QCT) was 32% on PTH(1-84) compared to 13% on alendronate (p < 0.0001). The higher variability in the PTH(1-84) group was due to substantial numbers of women with large increases in BMD on PTH(1-84). Similarly, the SD of changes in markers of formation and resorption were significantly higher on PTH(1-84) than on ALN. No baseline participant characteristics predicted increased bone density response to PTH(1-84) therapy. However, change in 1,25-OH(2)D explained 16% of the variance in BMD response to PTH(1-84)., Conclusion: There is significant variability in the skeletal response to PTH(1-84), which exceeds that observed with alendronate. Changes in 1,25-OH(2)D were related to larger gains in BMD. This finding may have implications for elucidating either the pathway by which PTH affects the skeleton or traits that result in particular responsiveness to PTH therapy.

By conventional 2-dimensional, histomorphometric analysis, we and others have previously shown that cancellous bone architecture is preserved in mild primary hyperparathyroidism (PHPT). We have now extended these observations to a 3-dimensional analysis using microcomputed tomography (microCT). Iliac crest bone biopsies were analyzed from the following subjects with PHPT: 22 postmenopausal women; 7 premenopausal women; similar numbers of normal pre- and postmenopausal women served as controls. Fifteen men with PHPT were also studied. Postmenopausal women with PHPT demonstrated features of preserved cancellous bone as shown by smaller age-related declines in cancellous bone volume (BV/TV) and connectivity density (Conn.D) and no change in bone surface/total volume (BS/TV) as compared to normal women. In postmenopausal women with PHPT, cancellous bone volume (BV/TV), bone surface/total volume, and connectivity density (Conn.D) were all higher, and trabecular separation (Tb.Sp) was lower than in postmenopausal controls. In sharp contrast to the findings in normal women, no structural variables in PHPT women were correlated with age. Also of note, there was no difference in any 3-dimensional index between women and men with PHPT. We conclude that three-dimensional, cancellous bone microarchitecture is preserved in patients with mild primary hyperparathyroidism.

Zoledronic acid inhibits bone resorption for up to 12 months. It is not known whether the duration of this antiresorptive effect extends beyond this period of time. The aim of this study was to evaluate the changes in bone turnover at 12 months (T12) and 18 months (T18) after a single injection of 4 mg of zoledronic acid. It is a prospective, longitudinal study, with a follow-up for 18 months. We studied male and female patients (60.5 +/- 11.0 years old), with low bone mineral density (BMD) coming from the outpatient clinic in a metabolic bone unit of a tertiary care hospital. All patients received a single intravenous dose of 4 mg of zoledronic acid, bone turnover markers [serum carboxyterminal telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase (BSAP)] and BMD [lumbar spine (LS) and total hip (TH)] were measured at baseline, and after 12 months (T12) and 18 months (T18). Median serum CTX-I and BSAP levels were suppressed at T12 in comparison with baseline values: 0.183 to 0.039 ng/ml for CTX-I (p = 0.0002) and 16.95 to 13.96 U/l for BSAP (p = 0.005). At T18, both CTX-I and BSAP continued to be suppressed below baseline at 0.108 ng/ml and 12.23 U/l (p = 0.009 and p = 0.02, vs. T0). Significant increases in BMD at T18 as compared with T12 were observed in patients (median increase 6.1% for LS and 2.0% for TH). Zoledronic acid inhibits bone turnover effectively for 12 months, with evidence for continued suppression and gains in BMD even after 18 months.

Summary: Few data are available regarding bone mineral density (BMD) and its determinants among Chinese Americans. We identified determinants of BMD among 359 Chinese-American women in order to identify risk factors for low BMD in this burgeoning population. BMD in Chinese-American women is influenced by a number of factors, including immigration., Introduction: Osteoporosis and low BMD are common among Chinese women, including Chinese Americans, who are a growing population at risk for osteoporosis in the US. Few data are available regarding BMD and its determinants among Chinese-American women., Methods: In this study, we examined predictors of BMD in 359 ambulatory Chinese-American women, ages 20-90, using stepwise multiple regression analysis. Variables in the model included age, weight, height, menarche age, years since menopause, immigration age, years in US, percentage of life in US, number of pregnancies, oral contraceptive use, family history of osteoporosis, family history of hip fracture, daily calcium intake, exercise, time outdoors, alcohol consumption and tobacco use., Results: Among premenopausal women, weight was the strongest predictor of BMD, accounting for 10.5% of the variance at the lumbar spine (LS), 15.2% at the total hip (TH) and 16.6% at the femoral neck (FN). Time outdoors was also a positive predictor of BMD (1.4% at LS, 2.8% at TH and 1.6% at FN), while family history of osteoporosis (1.4% at TH) and age (3.7% at FN) were negative predictors. Among postmenopausal women, greater BMD at the LS and TH was associated with greater weight and earlier immigration age. Weight accounted for 16.4% of the variance at the LS and 19.8% at the TH; immigration age accounted for 3.1% of the variance at the LS and 4.1% at the TH. At the FN, years since menopause and weight were predictors of BMD, accounting for 14.4% and 8.7% of the variance, respectively. While older age at immigration had a negative effect on BMD, years in and proportion of life in the United States were not significant predictors of BMD., Conclusions: Bone mineral density in Chinese-American women is influenced by a number of biological and lifestyle factors, including immigration. The results of this study provide new insights into risk factors for low bone density as they relate to environmental determinants in the growing population of Chinese-American women.

Introduction: While osteoporosis is common among women of Chinese descent, a readily available bone mineral density (BMD) referent database for Chinese American women does not exist. Fracture risk among this population is currently assessed using a Caucasian reference as well as diagnostic criteria for osteoporosis developed for postmenopausal Caucasian women. Many studies indicate that there are important racial differences in skeletal health and fracture risk, an observation that makes the application of Caucasian data to all groups problematical. This study was undertaken to establish a BMD referent database in Chinese American women and to compare it with a Caucasian female database. It is expected that a race-specific database will be useful in the assessment of bone health for Chinese American women., Methods: Healthy Chinese American women (n=359), ages 20-90, were recruited. Along with dual-energy X-ray absorptiometry (DXA) of the total hip and lumbar spine, demographic, medical, familial, nutritional, and behavioral data were obtained. The mean and standard deviation for BMD at each site was calculated for each 10-year age group and compared to mean BMD values for Caucasian women supplied as found in the Hologic DXA instrument. Osteoporosis diagnosis rates for this cohort, calculated with the Caucasian and newly established Chinese American BMD referent values, were compared with each other., Results: Compared with Caucasian women, Chinese American women have significantly lower BMD at the lumbar spine, total hip, and femoral neck across a wide spectrum of age groups. As a consequence, more than one-half of Chinese American women>or=50 years of age, who would be characterized as osteoporotic using a Caucasian referent, would not be diagnosed as such if a Chinese American referent were utilized., Conclusion: Chinese American reference BMD values are significantly lower than those for Caucasian women. Future studies relating Chinese American BMD values to fracture risk are necessary in order to determine if ethnic database-derived T-scores would be more predictive of fracture risk and to develop meaningful diagnostic criteria for this population.

The quest for effective treatment of osteoporosis merits great attention because of the widespread, worldwide prevalence of this disease. Antiresorptive drugs reduce bone turnover, increase bone density and improve other aspects of bone quality. This article concentrates on another approach, namely the use of anabolic therapy in which the prospects for improving bone quality are even greater. Parathyroid hormone is available as the aminoterminal fragment, PTH(1-34), known as teriparatide, and is being studied in its full-length form, PTH(1-84). Teriparatide improves bone quality by actions on bone turnover, bone density, bone size and microarchitecture. In women, teriparatide reduces both vertebral and non-vertebral fractures. In individuals who have been treated previously with an antiresorptive agent, the ability of PTH to increase bone density may be reduced. Combination therapy with teriparatide or PTH(1-84) and an antiresorptive does not appear, at this time, to offer advantages over the use of parathyroid hormone alone. In order to maintain the densitometric gains in bone density with parathyroid hormone, it is important to follow its use with an antiresorptive agent.

Anabolic effects of PTH have been observed at several skeletal sites in humans by dual x-ray absorptiometry without differentiating between an actual increase in bone volume and an increase in mineral content within already established bone. The present study addressed this issue by evaluating the bone mineralization density distribution of iliac crest bone biopsies before and after PTH treatment for 18-36 months in men and women with osteoporosis using quantitative backscattered electron imaging. In cortical bone, pairwise comparison of the two biopsies before and after treatment revealed a reduction in the typical calcium concentration in men (-3.32%; P = 0.02, by paired t test), but no change in women, and the heterogeneity of mineralization increased in both males and females [+18.80% (P = 0.09) and +18.14% (P = 0.005), respectively]. In cancellous bone, there was no change in the typical calcium concentration, but there was a greater heterogeneity of mineralization in both men and women [+19.65% (P = 0.02) and +21.59% (P = 0.056), respectively] due to newly formed bone matrix. Small angle x-ray scattering performed on a subgroup of subjects revealed normal collagen/mineral structure. The findings confirm the observations that PTH stimulates skeletal remodeling, resulting in an increased percentage of newly formed bone matrix of lower mineral density.

Definable causes of male osteoporosis account for only about 60% of the osteoporotic population. Those for whom no etiology is readily apparent are said to have primary or idiopathic male osteoporosis. In these individuals, histomorphometric studies indicate that this is a disorder that is more typically characterized by low turnover. Although antiresorptive agents such as alendronate have been shown to increase bone mass in men, the rationale for an anabolic agent that can stimulate bone formation is clear. The most attractive anabolic agent at this time is parathyroid hormone (PTH) administered in low dosage and intermittently. Such regimens in experimental animals have been associated with marked gains in bone mass. Slovik et al. showed that parathyroid hormone can increase vertebral bone mass in men with idiopathic osteoporosis. We have conducted the first controlled, randomized, double-blind study of PTH in men with idiopathic osteoporosis. Twenty-three men, 30-68 years old (50 +/- 1.9) with Z-scores less than -2.0 were assigned to a placebo (n = 13) or treatment (n = 10) arm. After 18 months, those who received PTH showed a 13.5 +/- 3% increase in bone mass, significantly greater than the placebo group whose bone density did not change. Femoral neck bone density increased significantly by 2.9 +/- 1.5%. The distal radius site did not change. During an open label extension for an additional 12 months, there was no further increase in bone density in the lumbar spine but the femoral neck continued to show gains. Markers of bone formation and resorption increased in the PTH arm reaching a peak between 9 and 12 months of therapy and declining thereafter. Parathyroid hormone was well tolerated. These results suggest that low-dose intermittent PTH may be an efficacious therapy for men with idiopathic osteoporosis.

We examined paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant, human parathyroid hormone 1-34 [PTH(1-34)]. Two groups of patients were studied. The first group was comprised of 8 men with an average age 49 years. They were treated with PTH for 18 months. The second group was comprised of 8 postmenopausal women with an average age 54 years. They were treated with PTH for 36 months. The women had been and were maintained on hormone replacement therapy for the duration of PTH treatment. Patients were supplemented to obtain an average daily intake of 1500 mg of elemental calcium and 100 IU of vitamin D. The biopsy specimens were subjected to routine histomorphometric analysis and microcomputed tomography (CT). Cancellous bone area was maintained in both groups. Cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the inner aspect of the cortex in both men and women. This was accompanied by a significant decrease in eroded perimeter on this surface in both groups. Micro-CT confirmed the foregoing changes and, in addition, revealed an increase in connectivity density, a three dimensional (3D) measure of trabecular connectivity in the majority of patients. These findings indicate that daily PTH treatment exerts anabolic action on cortical bone in patients with osteoporosis and also can improve cancellous bone microarchitecture. The results provide a structural basis for the recent demonstration that PTH treatment reduces the incidence of osteoporosis-related fractures.

Parathyroid hormone (PTH) activates both adenylyl cyclase and phospholipase C via the PTH-1 receptor. We previously reported that PTH increased heart rate and that this effect was mediated via the pacemaker current (I f ). However, it has been reported that PTH exerts its chronotropic effect via an interaction with adrenergic receptors or via L-type calcium channels. Thus, the objective of the study was to elucidate the exact mechanism of the chronotropic effect of PTH. We tested whether its chronotropic effects could be abolished by inhibitors of the following systems in isolated perfused rat hearts: alpha-adrenergic (prazosin); beta-adrenergic (propranolol); angiotensin II (CV11974); endothelin-1 (TAK044); calcium channel (verapamil); adenylyl cyclase (miconazole); phospholipase C (U73122) or I f (CsCl). In addition, we measured the cyclic adenosine monophosphate level of the heart after PTH administration. Whereas prazosin, propranolol, CV11974, TAK044, verapamil, and U73122 did not inhibit the chronotropic effect of PTH, CsCl or miconazole suppressed it significantly. PTH increased the cyclic adenosine monophosphate level of the atrium but not the left ventricle. These results indicate that the chronotropic actions of PTH are mediated via selective activation of adenylyl cyclase to increase the I f current.

Different regions within the parathyroid hormone (PTH) molecule are known to have different biological activities. In the heart, the physiological actions of the intact PTH molecule are known as positive chronotropy and coronary vasodilatation. However, it is unclear which region of the PTH exerts which physiological action in the heart. Therefore, to clarify this point, we examined the hemodynamic effect of intact PTH(1-84) and selected PTH analogs, namely, PTH(1-34), PTH(2-34), [Nle8, 18Tyr34]PTH(3-34), PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34) in isolated perfused rat hearts. Both PTH(1-84) and PTH(1-34) significantly increased heart rate and decreased coronary perfusion pressure. In contrast, neither PTH(2-34) nor [Nle8,18Tyr34]PTH(3-34) increased heart rate, but they did decrease coronary perfusion pressure. Peptides further truncated at the amino terminus, PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34), had no effect on hemodynamics. Furthermore, the protein kinase A inhibitor H89, but not the protein kinase C inhibitor H7, attenuated the hemodynamic effects of PTH(1-34) or PTH(2-34), while it prevented those of [Nle8,18Tyr34]PTH(3-34). These results clearly demonstrate that the first amino acid of PTH is essential for its chronotropic property whereas the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A, but not protein kinase C, appears to be involved in the chronotropic and coronary vasodilatory actions of PTH.

All currently available, approved therapies for osteoporosis inhibit bone resorption. By acting at this site in the bone remodeling cycle, estrogens, selective estrogen receptor modulators, calcitonin, and the bisphosphonates all have the capacity to increase bone mineral density and to reduce the risk of new fractures. There can be no doubt that these agents have had an enormous impact on our diagnostic and therapeutic approach to osteoporosis. Despite their great value, the antiresorptives are generally not associated with dramatic increases in bone mass, and their action to reduce fracture risk, although highly significant, is rarely more than 50% of the baseline risk. Another approach is anabolic therapy, in which bone formation is directly stimulated. In this review we will summarize the anabolic agents that have been studied and present a current view of their current standing. Fluoride, GH, insulin-like growth factor I, the statins, and PTH will be reviewed. Although still in development, approaches to combination therapy with antiresorptives and anabolic agents are also promising.

The developing human skeleton is known to be influenced by the presence of sex steroids. In girls, estrogens have been considered to be the dominant hormone, whereas in boys, androgens have occupied a primary physiological role in terms of bone mass accrual. Although these views are still current, recent observations made of rare defects in estrogen receptor sensitivity or estrogen synthesis have called attention to the importance of estrogens in the developing male skeleton. In these human genetic models, the affected men have demonstrated continuous linear skeletal growth, open epiphyses, lack of pubertal growth spurt, and reduced bone mass. In the example of men with aromatase deficiency, lacking estrogens from birth, administration of estrogen led to impressive increases in bone density, maturation of the skeletal growth plates, and cessation of linear growth. Animal models mimicking these human syndromes by knockout technology, have tended to support these observations. The data argue for a primary role of estrogens in the developing male skeleton, while not diminishing the important role for androgens.

A young man with previously unrecognized Graves' disease presented with atrial fibrillation and severe low-output heart failure due to dilated cardiomyopathy. The patient's cardiomyopathy resolved and cardiac function recovered shortly after hyperthyroidism and tachycardia were treated during hospitalization. The temporal relationship between heart rate and cardiac function during the recovery period suggests that chronic tachycardia may have been an important cause of his cardiac dysfunction. Thyrotoxicosis seemed to be directly responsible for the development of sustained supraventricular tachycardia in this patient, which then led to tachycardia-induced cardiomyopathy causing severe low-output heart failure. Although relatively infrequent, this etiology should not be overlooked in patients thyrotoxicosis and heart failure. This is the first case in which the time course and the temporal relationship between the control of heart rate and the recovery of cardiac function are illustrated in a thyrotoxic patient.

To a certain extent, the emphasis placed on women in light of the predominance of osteoporosis in this sex is well-justified. As researchers are appreciating the potential size of the male population at risk for osteoporosis, increasing interest is becoming apparent on the part of investigators and the pharmaceutical companies that are developing therapies. As more is learned about osteoporosis in men, experts will then be in a position to better understand the similarities and differences between genders.

Osteoporosis in men poses a unique therapeutic challenge. Clinical studies have focused largely on the more prevalent problem of post-menopausal osteoporosis, with few gender-specific studies exploring treatment options in men. Idiopathic osteoporosis in middle-aged men presents an additional dilemma, because in the majority of patients it is a low bone turnover state for which there are currently no available anabolic agents. We conducted an 18-month randomized, double blind, placebo-controlled trial of 23 men with idiopathic osteoporosis, 30-68 yr old (mean age +/- SEM, 50 +/- 1.9 yr). All patients received 1,500 mg calcium and 400 IU vitamin D daily. Ten patients were randomized to receive 400 IU PTH-(1-34), and 13 patients received vehicle, administered by daily sc injection. Serum and urinary biochemistries, including markers of bone turnover were measured every 3 months. Bone densitometry of the lumbar spine, hip, and radius was performed every 6 months. PTH-(1-34) was associated with a marked 13.5% increase in bone mass at the lumbar spine, whereas that in the control group did not change (P < 0.001). The mean lumbar spine T-score improved from -3.5 +/- 0.2 to 2.4 +/- 0.4. Femoral neck bone mineral density in the PTH-treated group increased 2.9% (P < 0.05). The 1/3 site of the distal radius showed no change from baseline in the PTH-treated group. There were no significant changes in serum calcium concentration, 24-h urinary calcium excretion, or 1,25-dihydroxyvitamin D in either group. All markers of bone turnover increased in the PTH-treated patients, with the greatest changes in serum osteocalcin and urinary N-telopeptide (230% and 375% above baseline by 12 months, respectively; P < 0.001). Free pyridinoline and markers of bone formation that showed little correlation with each other at baseline, became highly correlated in the PTH-treated group (r = 0.1; P = 0.29 at baseline; to r = 0.7; P < 0.0001 at 18 months), a pattern absent in the control patients. The best predictor of the lumbar spine response to PTH at 18 months was the combination of pyridinoline at baseline and osteocalcin at 3 months (70% of the variance). PTH is a potent stimulator of skeletal dynamics in men with idiopathic, low turnover osteoporosis; is associated with substantial increases in lumbar spine and hip bone density; and may prove to be an efficacious anabolic agent in men with this disorder.

Of the many functions that parathyroid hormone serves, none is more important than its role to maintain calcium homeostasis. Intrinsic to the aging process is changes in the synthesis, metabolism, and responsiveness of parathyroid hormone. This article explores whether the age-associated changes in parathyroid hormone are causally related to the age-associated changes in bone mass. On the other hand, some of the apparent changes in parathyroid hormone associated with aging may be adaptive, serving to protect the aging skeleton. More information is needed to sort out these diametrically opposite views.

The decision to recommend parathyroid surgery in patients with symptomatic primary hyperparathyroidism is clear. The decision to recommend parathyroid surgery in patients with asymptomatic primary hyperparathyroidism is clearer than it was 10 years ago. In addition to the NIH guidelines, the author believes that patients who have vertebral osteopenia, patients who have vitamin D deficiency, and patients who are in their perimenopausal years should undergo surgery. Although surgery may be an acceptable option even for patients who do not meet these guidelines, many patients can be safely managed without surgery. For these patients, monitoring is essential because a small number will show progression of disease over time.

Primary hyperparathyroidism has been associated with bone loss, especially at cortical skeletal sites. Results from studies evaluating the mineral density of cancellous bone have been more difficult to interpret. Most densitometry studies support the concept that the parathyroid hormone appears to be catabolic at cortical sites and may have anabolic effects at cancellous bone sites. Studies completed to date, however, have been limited by design, definitions of fracture and inadequate control groups. Primary hyperparathyroidism is now increasingly being detected during the asymptomatic phase. The need for parathyroidectomy has been questioned in such patients because there may be no disease progression in the absence of surgery. Medical management of primary hyperparathyroidism has to date been limited to estrogen replacement therapy in postmenopausal women. Identification of the calcium receptor has improved our understanding of calcium homeostasis, and significant reductions in calcium receptor levels have been detected in parathyroid adenomas. Thus, a new class of therapeutics may include the calcimimetic agents. Bisphosphonates are also currently being evaluated with regard to their impact on fracture prevention and their beneficial effects on bone mineral density.

Objective: To characterize the historical, clinical, and biochemical features of 111 young women (age, <55 years) referred for evaluation of osteoporosis or low bone mass., Methods: Women with a bone mineral density T score < or = -2.0 (N = 111) at one or more anatomic sites (by dual-energy x-ray absorptiometry) were assessed relative to anthropomorphic and biochemical characteristics and risk factors for osteoporosis., Results: Of 111 women with low bone mass or osteoporosis, 73 (66%) had identifiable causes of bone loss, of which estrogen deficiency (menopause, premenopausal estrogen deficiency) and conditions associated with estrogen deficiency (anorexia nervosa, cancer chemotherapy) were the most common. Prolonged use of glucocorticoids was the most common secondary cause of osteoporosis. Of 38 women with no identifiable cause of bone loss, 21 were premenopausal (mean age, 38 +/- 10 years [standard deviation]) and 17 were perimenopausal (mean age, 50 +/- 3 years). The mean lumbar spine T score was -2.18 +/- 1.0 in the premenopausal and -2.51 +/- 0.6 in the perimenopausal women. Nontraumatic fractures were reported by 42% of the premenopausal women and 18% of the perimenopausal women. A family history of osteoporosis was reported by 71% of the premenopausal and 47% of the perimenopausal women., Conclusion: Most young women with osteoporosis or low bone mass had estrogen deficiency or another secondary cause of premature bone loss (or both). A subset of premenopausal and perimenopausal women, however, had no identifiable cause of bone loss. The strong family history of osteoporosis, especially in the premenopausal women, provides further support for current theories of a genetic predisposition to osteoporosis.

The Western world has been used to describing disease on its terms, as if it is a prototype for the same disease found anywhere else in the world. It is unusual that one can test the hypothesis that a common disease can present in markedly different ways, depending on the country in which it is studied. We have had the opportunity to compare and contrast primary hyperparathyroidism in the United States and in China as seen in New York City and in Beijing. The cohort of subjects in each case was well over 100, and the experience extends to well over a decade of observations. In the United States, primary hyperparathyroidism typically presents as asymptomatic hypercalcemia in women within 10 years of menopause. Most often, it is discovered accidentally in the course of a routine multichannel chemistry screening test. The serum calcium is 10.5 + 0.1 mg/dL, within 1 mg/dL above the upper limit of normal, 10.2; the serum parathyroid hormone level is 118 + 9 pg/mL (within 1.5-2-fold above the normal limit, 65). The average 25-hydroxyvitamin D level is 21 ng/mL, in the lower range of normal. The classical clinical manifestations of primary hyperparathyroidism, stone and bone disease, have become much less common than earlier descriptions of the disease in the United States through the 1950s. Overt radiological bone disease (osteitis fibrosa cystica) is almost never seen, whereas stone disease is reduced in incidence from a high of 60% in the 1940s to current estimates of 15-20% now. Most patients are asymptomatic; skeletal involvement is detected only by measuring skeletal calcium by bone densitometry. Primary hyperparathyroidism in China presents much differently. Patients are younger, with an average age of 37. The serum calcium level is much higher, averaging about 12 mg/dL. PTH is over 20 times the upper limits of normal. The average 25-hydroxyvitamin D concentration is much lower than in the United States population, 8.8 ng/mL. Radiological evidence for osteitis fibrosa cystica is seen in 60% of patients; virtually all patients have osteoporosis. Thirty-five percent of patients suffer pathological fractures, most often of the femur or humerus. Forty-two percent demonstrate kidney stones, with half showing bilateral disease. Constitutional features of weakness and easy fatigability are always present. There are both facile and rather subtle explanations for this dramatically different presentation of the same disease in the United States (New York City) and China (Beijing).

It is now possible to measure bone mass with highly precise, safe and noninvasive technology. Dual energy X-ray absorptiometry (DXA) can detect bone loss well before it becomes evident by conventional X-rays or by fracture. Because measurement of bone density is the single most important predictor of fracture risk, it is a critically important tool to apply to the population at risk, which includes women who have definable risk factors for osteoporosis, such as the menopause, as well as those with a family history of osteoporosis, life-long low calcium intake, smoking, extreme thinness, anorexia, certain diseases and medications. Central DXA machines measure bone mass of the lumbar spine and hip region, the most important potential fracture sites. At the present time, the number of DXA machines in the United States is inadequate to detect the entire population at risk. Even if there were a sufficient number of DXA machines, lack of insurance reimbursement would limit their use. These restraints are beginning to be better defined, if not moderated, by the Bone Mass Measurement Act of 1998. With insufficient numbers of DXA machines and their heavy localization to major urban medical centers, peripheral devices have been developed. Using DXA technology, these peripheral devices can measure densities in the distal forearm, the middle phalangeal bone, and the heel. Ultrasound technology has also been developed to measure bone density of the tibia and the heel. The peripheral densitometers, in general, have the advantage of smaller size, lower cost, and portability. A very controversial issue, however, is whether measurement at a peripheral site provides sufficiently accurate information about bone mass at more important central sites to be generally reliable. Nevertheless, they have great potential in helping to detect the large numbers of women at risk for osteoporosis. Eventually, however, central measurements of bone mass will be needed, especially for monitoring of therapy, so that central measurements of bone mass by DXA are still the "gold standard" in the field at this time.

Biochemical markers of bone turnover have emerged as powerful tools to aid in managing osteoporosis. The newer bone markers have been intensively studied for more than a decade. As a result, we can now confidently report their clinical utility in assessing risk of rapid bone loss and fracture, and monitoring therapy in postmenopausal women with or at risk of osteoporosis. In this review, we will provide a comprehensive foundation for this utility. While there are still questions remaining to be answered, bone marker technology has matured to play an essential role in patient management. We will describe, in practical terms, how bone markers can be appropriately incorporated into clinical practice today.

There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.