Ann E. Kearns

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.

Medical and Surgical Management of Hyperparathyroidism

Hypercalcemia is frequently encountered in healthy outpatients. Reliable measurements of the mediators of hypercalcemia have improved diagnostic certainty about the etiology in most patients. Hyperparathyroidism is overwhelmingly the most common cause. Medical evaluation of the patient with hyperparathyroidism requires an understanding of the complications of the disorder and the associated syndromes. At present decreased bone mineral density and nephrolithiasis are the major sequelae of hyperparathyroidism. Most cases of primary hyperparathyroidism are sporadic; however, hereditary forms can occur in patients with the multiple endocrine neoplasia syndromes. Surgery is the only curative therapy. Results are excellent when an experienced endocrine surgeon performs parathyroid surgery.

Depression in Primary Hyperparathyroidism: Prevalence and Benefit of Surgery

CONTEXT Patients with primary hyperparathyroidism (PHP) often report nonspecific symptoms including mood disturbances. OBJECTIVE The objective of the study was to determine the frequency of depression in PHP and assess its response to parathyroidectomy. METHODS A case-control study at a referral center in Rochester, MN, performed Patient Health Questionnaire-9 (PHQ-9) assessments in observed (n = 81) and surgical (n = 88) PHP and benign nontoxic surgical thyroid disease (n = 85) at baseline and 1, 3, 6, and 12 months after surgery or the initial questionnaire in observed PHP. Baseline PHQ-9 scores and their response to surgery were evaluated. RESULTS The groups were similar in gender and depression history, but PHP patients were older. Baseline PHQ-9 scores were 1.71 points higher in PHP than controls after adjusting for age and gender (P = .004). Clinically significant PHQ-9 scores (≥10) were twice as common in PHP (31.4%) compared with thyroid subjects (15.3%). Parathyroidectomy resulted in significant and sustained reductions in PHQ-9 scores, which were greater than observed PHP at all time points (P < .001). PHP patients with clinically significant PHQ-9 scores dropped to 7.4% (P < .001) and 7.6% (P < .001) at 1 month and 1 yr after parathyroidectomy. There were greater declines in PHQ-9 scores after parathyroidectomy at 1, 3, and 6 months (P < .001) and 1 yr (P = .061) compared with thyroid surgery. CONCLUSIONS Depression is common in patients with PHP. Parathyroidectomy results in greater improvement in PHQ-9 scores compared with thyroid surgery or observation of PHP.

Abdominal Aortic Calcification, BMD, and Bone Microstructure: A Population-Based Study

To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age‐stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high‐resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and ≥50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age‐dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex‐specific differences exist.

Fluoride-related bone disease associated with habitual tea consumption

Acquired osteosclerosis is a rare disorder of bone formation but an important consideration in adults with sclerotic bones or elevated bone density results. In such patients, malignancy, hepatitis C, and fluorosis should all be considered when making a diagnosis. We describe 4 patients evaluated at our Metabolic Bone Disease Clinic from May 1, 1997, to July 1, 2006, whose bone disorders resulted from chronic fluoride exposure due to excessive tea intake. Three of these patients had toxic serum fluoride levels (> 15 micromol/L). Although the clinical presentation of the patients varied, all 4 had an unexpectedly elevated spine bone mineral density that was proportionately higher than the bone mineral density at the hip. Other clinical features included gastrointestinal symptoms such as nausea, vomiting, and weight loss; lower extremity pain sometimes associated with stress fractures of the lower extremities; renal insufficiency; and elevated alkaline phosphatase levels. Readily available, tea often contains high levels of fluoride. Obsessive-compulsive drinking behaviors and renal insufficiency may predispose to excessive fluoride consumption and accumulation. The current cases show that fluoride-related bone disease is an important clinical consideration in patients with dense bones or gastrointestinal symptoms and a history of excessive tea consumption. Furthermore, fluoride excess should be considered in all patients with a history of excessive tea consumption, especially due to its insidious nature and nonspecific clinical presentation.

Secular trends in the incidence of primary hyperparathyroidism over five decades (1965-2010)☆

Introduction of automated serum calcium measurements in the 1970s resulted in a sharp rise in primary hyperparathyroidism (PHPT) incidence. However, recent investigations suggest a significant rise in PHPT incidence for unclear reasons. Our objective was to update our population-based secular trends in PHPT incidence, to determine if there has been a significant rise in PHPT incidence as suggested by others, and, if possible, to identify changes in clinical practice that might be responsible. Rochester, Minnesota, residents who met the criteria for PHPT from 2002 through 2010 were identified through the medical records-linkage system of the Rochester Epidemiology Project and added to the historical cohort beginning in 1965. Incidence rates were adjusted to the 2010 US white population. Altogether, 1142 Rochester residents have been diagnosed with PHPT since 1965, including 341 in 2002-2010. Over time, two periods of increased PHPT incidence occurred, one beginning in 1974 (121.7 per 100,000 person-years) and a second peak (86.2 per 100,000 person-years) starting in 1998. The median age of PHPT subjects has increased significantly from 55 years in 1985-1997 to 60 years of age in 1998-2010 and more patients (36%) had a parathyroidectomy in 1998-2010. Although serum calcium measurement has declined since 1996, there was a progressive increase in parathyroid hormone testing between 1994 and 2008. There was also a rise in orders for bone mineral density measurements in women since 1998, which peaked in 2003-2004. A second sharp rise in PHPT incidence occurred in our community in 1998, simultaneously with the introduction of national osteoporosis screening guidelines, Medicare coverage for bone density measurement, and new medications for the treatment of osteoporosis. Case ascertainment bias from targeted PHPT screening in patients being evaluated for osteoporosis is the most likely explanation.

Effects of Estrogen with Micronized Progesterone on Cortical and Trabecular Bone Mass and Microstructure in Recently Postmenopausal Women

CONTEXT In women, cortical bone mass decreases significantly at menopause. By contrast, loss of trabecular bone begins in the third decade and accelerates after menopause. OBJECTIVE The aim of the study was to investigate the effects of estrogen on cortical and trabecular bone. DESIGN The Kronos Early Estrogen Prevention Study is a double-blind, randomized, placebo-controlled trial of menopausal hormone treatment (MHT) in women, enrolled within 6-36 months of their final menstrual period. SETTING The study was conducted at the Mayo Clinic, Rochester, Minnesota. INTERVENTION Subjects were treated with placebo (n = 31), or .45 mg/d conjugated equine estrogens (n = 20), or transdermal 50 μg/d 17β-estradiol (n = 25) with pulsed micronized progesterone. MAIN OUTCOME MEASURES Cortical and trabecular microarchitecture at the distal radius was assessed by high-resolution peripheral quantitative computed tomography. RESULTS At the distal radius, cortical volumetric bone mineral density (vBMD) decreased, and cortical porosity increased in the placebo group; MHT prevented these changes. By contrast, MHT did not prevent decreases in trabecular microarchitecture at the radius. However, MHT prevented decreases in trabecular vBMD at the thoracic spine (assessed in a subset of subjects; n = 51). These results indicate that MHT prevents deterioration in radial cortical vBMD and porosity in recently menopausal women. CONCLUSION The maintenance of cortical bone in response to estrogen likely has important clinical implications because cortical bone morphology plays an important role in bone strength. However, effects of MHT on trabecular bone at the radius differ from those at the thoracic spine. Underlying mechanisms for these site-specific effects of MHT on cortical vs trabecular bone require further investigation.

Changes in bone mineral density after surgical intervention for primary hyperparathyroidism

BACKGROUND Patients with primary hyperparathyroidism often lack classic symptoms but can have reductions in bone mineral density and increased fracture risk. We sought to determine bone mineral density improvement after successful surgery and associated factors. METHODS A review of patients with osteopenia or osteoporosis with curative parathyroidectomy and both pre- and postoperative dual-energy X-ray absorptiometry bone mineral density scans was conducted. We compared patients with declining (<0%), moderate improvement (0.1-5%), and significant improvement (>5%) on dual-energy X-ray absorptiometry bone mineral density scans. RESULTS We identified 420 patients who underwent a dual-energy X-ray absorptiometry bone mineral density scan preoperatively and within 36 months postoperatively. At the most affected site, 38% had significant improvement, 31% moderate improvement, and 31% declining bone mineral density. Patients who significantly improved were younger (P = .01), had lesser preoperative dual-energy X-ray absorptiometry (P = .001), and had greater preoperative levels of parathyroid hormone (P = .04), serum calcium (P = .03), and preoperative urinary calcium. There was no difference in outcomes between sex and with preoperative bisphosphonate use. Average hip and spine bone mineral density had similar responses to surgery. CONCLUSION Bone mineral density improves in up to 75% of patients after curative parathyroidectomy for primary hyperparathyroidism. The hip and lumbar spine responded similarly. Younger patients and those with severe primary hyperparathyroidism may derive the most skeletal benefits from parathyroidectomy, but the uniform positive response supports parathyroidectomy in patients with osteoporosis and possibly osteopenia.

Relationship Between Low Bone Mineral Density and Exercise-Induced Myocardial Ischemia

OBJECTIVE To evaluate the relationship between bone mineral density (BMD) and ischemic heart disease and exercise capacity, as assessed by stress testing. PATIENTS AND METHODS We retrospectively reviewed entries in the echocardiography database for 28,048 consecutive patients who underwent exercise echocardiography for standard clinical indications between August 1, 1998, and October 1, 2003, to determine which of these patients had also undergone dual-energy x-ray absorptiometry to measure femoral neck BMD before the procedure. Of the 1194 patients meeting both criteria, 28 were excluded because of missing data and 24 because they were tested with an exercise protocol other than the Bruce protocol, leaving 1142 patients to be included. RESULTS Of the included study patients, 643 (56%) had a T score of -1.0 or less (mean age +/- SD, 67 +/- 0 years; 87% women), and 499 (44%) had a T score greater than -1.0 (60 +/- 10 years; 90% women). For every 1-unit decrease in femoral neck T score, a 0.23 minute decrease in treadmill exercise duration was observed, once values had been adjusted for age and other patient characteristics (95% confidence interval [CI], 0.11-0.35; P<.001). Furthermore, for every 1-unit decrease in T score, there was a 22% increased risk of myocardial ischemia after adjustments (hazard ratio, 1.22; 95% CI, 1.06-1.41; P=.004). Overall, after adjustments, patients with a BMD of -1.0 or less who were referred for exercise echocardiography had a 43% greater risk of myocardial ischemia than did patients referred with normal BMD (hazard ratio, 1.43; 95% CI, 1.06-1.94; P=.02). CONCLUSIONS Lower BMD is associated with myocardial ischemia and decreased exercise capacity during exercise echocardiography. Persons with low BMD who present with symptoms suggestive of cardiovascular disease are more likely to have myocardial ischemia than are those with normal BMD.

Osteoporosis associated with megestrol acetate.

Megestrol acetate is a progestational agent for treatment of metastatic breast cancer and endometrial cancer. Megestrol has also been used as an appetite stimulant for patients with human immunodeficiency virus and malignancy who experience cachexia and wasting; also, megestrol can be beneficial in relieving hot flashes in women and men. Megestrol has been shown to have a glucocorticoidlike effect and has been associated with substantial suppression of plasma estradiol levels. We describe 2 patients who recently presented to our Metabolic Bone Disease Clinic with severe osteoporosis complicated by multiple vertebral fractures experienced while the patients were receiving high-dose megestrol therapy. The patients had evidence of adrenal axis suppression but recovered fully after megestrol was discontinued. We speculate that megestrol was an important factor in the development of osteoporosis and subsequent fractures. Further study is warranted to clarify the relationship between megestrol and its potential for adversely affecting the skeleton.