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Recent advances in understanding skeletal metabolism has expanded the pharmacological options for treating osteoporosis in women. The antiresorptive or anticatabolic drugs are the oldest class known for their positive benefits in therapy. A better appreciation of their mode of action reveals much broader effects than formerly realized. It provides an entrée into understanding the actions of drugs on the qualitative elements of bone in addition to the quantitative ones on density. New bisphosphonates make for better patient adherence to therapy, a continuing problem in long-term care. A new class of drugs called anabolic agents, typified by teriparatide usher, has the potential to reconstitute destroyed bone and bring it to its pristine state. This article briefly focuses on where we were in this arena a mere decade ago and then highlights the new elements in therapy and physiology of the skeleton. A brief exposé on osteoporosis in men is also provided. [ABSTRACT FROM AUTHOR]

BACKGROUND: As a growing percentage of Americans will be reaching their elderly years in the next decade, the prevalence of osteoporosis and its effects will have an even greater impact on the healthcare system. Advancements in bone research and development of newer treatments have allowed for the establishment of more refined guidelines and a growing awareness of the need to prevent, screen, and diagnose osteoporosis. Thus, more women are now being screened with dual x-ray absorptiometry scans (DXA) than ever before. The importance of a true understanding of the test results obtained from such screening is paramount. In our institution, recommendations to consider a secondary evaluation are made by the DXA interpreters when the Z-score is low. Few, if any, studies have evaluated the rates of physician and patient adherence with specific recommendations provided on the bone density report. METHODS: To assess compliance with such recommendations provided in DXA interpretations, we investigated the number of ordering providers who actually pursued these advisements. RESULTS: We found that among providers ordering DXAs, primary care providers did not pursue recommendations to pursue a secondary workup as often as their subspecialty counterparts. We also found a significant amount of vitamin D deficiency/insufficiency and primary hyperparathyroidism in the population evaluated. CONCLUSIONS: Primary care providers should be further educated on treatable secondary causes of osteoporosis as opposed to an often reflexive response of prescribing a pharmacological antiresportive agent without other consideration. [ABSTRACT FROM AUTHOR]

The most common secondary form of osteoporosis is corticosteroid-induced disease. Cases of endogenous corticosteroid excess are few compared with the large number produced by exogenous use of the drug for management of many diverse diseases. Although headway has been made in diagnosis and management of the disease, the diagnosis is not made and treatment is not received in far too many patients. Bone densitometry is effective in estimating fracture risk when used for postmenopausal women, but the T-score may not detect patients receiving corticosteroids who are at risk. The pathology of the disorder is best understood at the molecular level. In turn, therapies are more appropriately used to counter the deleterious effects. [ABSTRACT FROM AUTHOR]

Dual-energy x-ray absorptiometry (DXA) can detect bone mineral density loss before it can be identified on usual skeletal radiography, making it possible to diagnose osteoporosis in postmenopausal women and older men before clinical fractures arise. However, when DXA is used outside these populations or if the clinical picture does not match the reported T-scores, mistakes can arise in interpreting results and determining the need for pharmaceutical therapy., (Copyright © 2021 The Cleveland Clinic Foundation. All Rights Reserved.)

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: High-quality dual-energy X-ray absorptiometry (DXA) scans are necessary for accurate diagnosis of osteoporosis and monitoring of therapy; however, DXA scan reports may contain errors that cause confusion about diagnosis and treatment. This American Association of Clinical Endocrinologists/American College of Endocrinology consensus statement was generated to draw attention to many common technical problems affecting DXA report conclusions and provide guidance on how to address them to ensure that patients receive appropriate osteoporosis care., Methods: The DXA Writing Committee developed a consensus based on discussion and evaluation of available literature related to osteoporosis and osteodensitometry., Results: Technical errors may include errors in scan acquisition and/or analysis, leading to incorrect diagnosis and reporting of change over time. Although the International Society for Clinical Densitometry advocates training for technologists and medical interpreters to help eliminate these problems, many lack skill in this technology. Suspicion that reports are wrong arises when clinical history is not compatible with scan interpretation (e.g., dramatic increase/decrease in a short period of time; declines in previously stable bone density after years of treatment), when different scanners are used, or when inconsistent anatomic sites are used for monitoring the response to therapy. Understanding the concept of least significant change will minimize erroneous conclusions about changes in bone density., Conclusion: Clinicians must develop the skills to differentiate technical problems, which confound reports, from real biological changes. We recommend that clinicians review actual scan images and data, instead of relying solely on the impression of the report, to pinpoint errors and accurately interpret DXA scan images., Abbreviations: AACE = American Association of Clinical Endocrinologists; BMC = bone mineral content; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; ISCD = International Society for Clinical Densitometry; LSC = least significant change; TBS = trabecular bone score; WHO = World Health Organization.

[This corrects the article DOI: 10.1100/2012/807438.].

The dose-response effects of exercise in reduced gravity on musculoskeletal health have not been well documented. It is not known whether or not individualized exercise prescriptions can be effective in preventing the substantial loss in bone mineral density and muscle function that have been observed in space flight and in bed rest. In this study, typical daily loads to the lower extremities were quantified in free-living subjects who were then randomly assigned to control or exercise groups. Subjects were confined to 6-degree head-down bed rest for 84 days. The exercise group performed individually prescribed 1 g loaded locomotor exercise to replace their free-living daily load. Eleven subjects (5 exercise, 6 control) completed the protocol. Volumetric bone mineral density results from quantitative computed tomography demonstrated that control subjects lost significant amounts of bone in the intertrochanteric and total hip regions ( p  < 0.0125), whereas the exercise group showed no significant change from baseline in any region ( p  > 0.0125). Pre-and post-bed rest muscle volumes were calculated from analysis of magnetic resonance imaging data. The exercise group retained a larger percentage of their total quadriceps and gastrocnemius muscle volume (- 7.2% ± 5.9, - 13.8% ± 6.1, respectively) than their control counterparts (- 23.3% ± 5.9, - 33.0 ± 8.2, respectively; p  < 0.01). Both groups significantly lost strength in several measured activities ( p  < 0.05). The declines in peak torque during repeated exertions of knee flexion and knee extension were significantly less in the exercise group than in the control group ( p  < 0.05) but work done was not significantly different between groups ( p  > 0.05). The decline in VO 2max was 17% ± 18 in exercising subjects ( p  < 0.05) and 31% ± 13 in control subjects ( p  = 0.003; difference between groups was not significant p  = 0.26). Changes in blood and urine measures showed trends but no significant differences between groups ( p  > 0.05). In summary, the decline in a number of important measures of musculoskeletal and cardiovascular health was attenuated but not eliminated by a subject-specific program of locomotor exercise designed to replace daily load accumulated during free living. We conclude that single daily bouts of exposure to locomotor exercise can play a role in a countermeasures program during bed rest, and perhaps space flight, but are not sufficient in their own right to ensure musculoskeletal or cardiovascular health.

Introduction: Bone loss due to weightlessness is a significant concern for astronauts' mission safety and health upon return to Earth. This problem is monitored with bone densitometry (DXA), the clinical tool used to assess skeletal strength. DXA has served clinicians well in assessing fracture risk and has been particularly useful in diagnosing osteoporosis in the elderly postmenopausal population for which it was originally developed. Over the past 1-2 decades, however, paradoxical and contradictory findings have emerged when this technology was widely employed in caring for diverse populations unlike those for which it was developed. Although DXA was originally considered the surrogate marker for bone strength, it is now considered one part of a constellation of factors-described collectively as bone quality-that makes bone strong and resists fracturing, independent of bone density. These characteristics are beyond the capability of routine DXA to identify, and as a result, DXA can be a poor prognosticator of bone health in many clinical scenarios. New clinical tools are emerging to make measurement of bone strength more accurate. This article reviews the historical timeline of bone density measurement (dual X-ray absorptiometry), expands upon the clinical observations that modified the relationship of DXA and bone strength, discusses some of the new clinical tools to predict fracture risk, and highlights the challenges DXA poses in the assessment of fracture risk in astronauts.

Introduction: Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system., Methods: We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated., Results: A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%., Discussion: The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

To find the rational intervals for bone mineral density screening, Gourlay et al (N Engl J Med 2012; 366:225-233) used T scores to calculate the time required for women age 67 and older with normal bone mineral density or osteopenia to progress to osteoporosis. They estimated that the screening interval for women with normal bone mineral density or mild osteopenia (T score -1.49 or higher) could be as long as 15 years. However, the investigators focused mainly on T scores and when these scores reached -2.5. In our opinion, the testing interval should be guided by an assessment of clinical risk factors and not just baseline T scores.

Bone densitometry was originally developed to diagnose a high risk for fragility fractures in older postmenopausal women who may have primary osteoporosis. Its widespread availability, however, has led to its use in healthy peri- and premenopausal patients and the unexpected findings of low bone density in this group of patients. Their low bone density caused much uncertainty about the likelihood of fracture risk and what treatment might be needed. Conceptually, bone density reflected bone strength, and so a low density reflected increased fracture risk. Clinical experience and the results of pivotal studies of therapy for osteoporosis suggested that bone density was only partly responsible for skeletal strength. Many structural and material properties of bone, not measured by bone density, made it resist fracturing. Clinical risk factors helped determine these characteristics, albeit imperfectly, and aided clinicians decide whether and what treatment was needed. But now, new fracture risk assessment protocols (namely, FRAX, the WHO risk assessment tool) are available to help resolve this dilemma. This paper reviews some of the clinical observations that led to rethinking the concept bone density and bone strength and how it changes the clinical approach to therapy for the healthy young patient., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Patients with inflammatory bowel disease (IBD) are at high risk of developing osteoporosis. Our objective was to determine the usefulness of IBD guidelines in identifying patients at risk for developing osteoporosis., Methods: We utilized institutional repository to identify patients seen in IBD center and extracted data on demographics, disease history, conventional, and nonconventional risk factors for osteoporosis and Dual Energy X-ray Absorptiometry (DXA) findings., Results: 59% of patients (1004/1703) in our IBD cohort had at least one risk factor for osteoporosis screening. DXA was documented in 263 patients with indication of screening (provider adherence, 26.2%), and of these, 196 patients had DXA completed ("at-risk" group). Ninety-five patients not meeting guidelines-based risk factors also had DXA completed ("not at-risk" group). 139 (70.9%) patients in "at-risk" group had low BMD, while 51 (53.7%) of "not-at-risk" patients had low BMD. Majority of the patients with osteoporosis (83.3%) missed by the current guidelines had low BMI. Multivariate logistic regression analysis showed that low BMI was the strongest risk factor for osteoporosis (OR 3.07; 95% CI, 1.47-6.42; P = 0.003)., Conclusions: Provider adherence to current guidelines is suboptimal. Low BMI can identify majority of the patients with osteoporosis that are missed by current guidelines.

Most patients with multiple myeloma or other monoclonal gammopathies present with anemia, hypercalcemia, or renal insufficiency. However, osteoporosis may be the first sign. Measuring the concentration and ratio of free light chains in the serum can help detect monoclonal gammopathy and help to differentiate myeloma-related bone loss from other secondary forms of osteoporosis.

We describe the case of a woman with hypophosphatasia previously exposed to bisphosphonate and subsequently treated with teriparatide (recombinant human PTH 1-34).A Caucasian woman sustained bilateral femur stress fractures when she was fifty years old, which widened despite use of calcium, vitamin D and risedronate for 2.5 years and required intramedullary rods for stabilization. Hypophosphatasia was diagnosed in the interim due to low serum alkaline phosphatase (ALP) (ALP 20 IU/L; normal (N), 40-150 IU/L) and high pyridoxal 5' phosphate (3400 nmol/L; N 18-175 nmol/L). She was referred for further management. On presentation, she had significant fracture site pain and generalized bone pain (weight bearing and non-weight bearing) - making her walker dependent at home and wheel chair dependent outside home.She could not sleep at night due to discomfort when she moved. Daily teriparatide injections, 20 mcg subcutaneously were prescribed.At 8-weeks follow-up, fracture site pain, weight-bearing and non weight-bearing pain improved significantly allowing ambulation for prolonged periods without assistance. She slept at night without discomfort. Improvement persisted during her entire treatment period. Radiographs taken at 4 and 16 months of treatment demonstrated healing of femur fractures.Biochemically, mean urine cross-link-N-telopeptide increased 11% as compared to her base-line, while bone specific alkaline phosphatase did not increase as expected.In conclusion, we observed an uncoupling of bone formation and resorption markers during her treatment period in the face of notable clinical and radiological improvement. Off-label use of teriparatide may help patients with hypophosphatasia.

Diagnostic criteria for postmenopausal osteoporosis using central dual-energy X-ray absorptiometry (DXA) T-scores have been widely accepted. The validity of these criteria for other populations, including premenopausal women and young men, has not been established. The International Society for Clinical Densitometry (ISCD) recommends using DXA Z-scores, not T-scores, for diagnosis in premenopausal women and men aged 20-49 yr, though studies supporting this position have not been published. We examined diagnostic agreement between DXA-generated T-scores and Z-scores in a cohort of men and women aged 20-49 yr, using 1994 World Health Organization and 2005 ISCD DXA criteria. Four thousand two hundred and seventy-five unique subjects were available for analysis. The agreement between DXA T-scores and Z-scores was moderate (Cohen's kappa: 0.53-0.75). The use of Z-scores resulted in significantly fewer (McNemar's p<0.001) subjects diagnosed with "osteopenia," "low bone mass for age," or "osteoporosis." Thirty-nine percent of Hologic (Hologic, Inc., Bedford, MA) subjects and 30% of Lunar (GE Lunar, GE Madison, WI) subjects diagnosed with "osteoporosis" by T-score were reclassified as either "normal" or "osteopenia" when their Z-score was used. Substitution of DXA Z-scores for T-scores results in significant diagnostic disagreement and significantly fewer persons being diagnosed with low bone mineral density.

Central dual-energy X-ray absorptiometry (DXA) is the gold standard for non-invasive measurement of bone mineral density (BMD). Using this value and subject demographics, DXA software calculates T-scores and Z-scores. Professional society guidelines for the management of osteoporosis are based on T-scores and Z-scores, rather than on the actual BMD value. Although one expects T-scores and Z-scores to be very similar in young men and women for any given BMD measurement, little literature exists on this issue. Our clinical experience shows that some younger adult individuals (premenopausal women and men younger than 50 yr) have larger than expected difference between their DXA T-score and Z-score. This cross-sectional study evaluates the extent of this discordance between Z-scores and T-scores in a sample of 4275 men and women aged 20-49 yr. All subjects were scanned by central DXA using equipment manufactured by GE Lunar, GE, Madison, WI, or Hologic, Inc., Bedford, MA. Significant differences between Z-scores and T-scores were seen within individuals at the lumbar spine, total hip, femoral neck, and trochanter (p value<0.001) for both DXA systems. Although these differences were less than half a standard deviation (SD) in most instances, the magnitude of difference was substantial at times, being 1 or more SD in up to 11% of cases (range: -1.95 to +1.54 SD). The smallest differences were seen at the total hip and the largest differences were seen at the femoral neck for both technologies. This is in part because there is no single standard Z-score definition, resulting in different methods of calculation across, and even within, DXA manufacturers. Standardization of Z-score definition and method of calculation is indicated. DXA Z-scores should be interpreted with caution in men and women aged 20-50 yr.

Introduction: Bone metabolism disturbances following renal transplantation (RT) are complex and multifactorial in origin. Abnormalities in 1,25-dihydroxyvitamin D levels in RT patients under treatment at our Bone Center prompted this retrospective study., Methods: Parameters of vitamin D metabolism were compared in RT patients and a cohort of patients with primary hyperparathyroidism (PHTP) who mimicked the hyperparathyroid state of the RT patients. Thirty-one RT recipients (from 300 reviewed) matched our inclusion criteria with a stable graft function for more than 1 year and a glomerular filtration rate (GFR) >50 mL/min per 1.73 m(2) (Group A); these were compared with 42 consecutive patients with PHTP who had been referred to the same Bone Center for treatment for over 1 month (Group B). Statistical analysis included the chi-square or Fisher's exact tests for categorical data and the Wilcoxon rank sum test for quantitative measures., Results: The mean (+/-SD) 1,25-dihydroxyvitamin D level was significantly lower (p < 0.001) in Group A patients (29.8 +/- 16.2) than in Group B patients (70.2 +/- 25.9) despite non-significant differences in the levels of parathyroid hormone (PTH) (mean: 184.0 vs.101.1;p < 0.29), phosphorus (mean: 3.2 vs. 3.1; p < 0.3) and 1,25-vitamin D (mean: 19.5 vs. 25.2; p < 0.06). Group A patients had lower levels (p < 0.05) of mean serum calcium and calculated GFR (9.3 mg/dL, 65.7 mL/min) than Group B patients (10.6 mg/dL, 97.6 mL/min). 1,25-Dihydroxyvitamin D significantly correlated with calcium (p < 0.001), 25-vitamin D (p < 0.005) and GFR (p < 0.001) in both groups, but there was a notable lack of association between 1,25-dihydroxyvitamin D and PTH (p < 0.64) or phosphorus (p < 0.26) in Group A patients. In this group, 1,25-dihydroxyvitamin D was not influenced by the type of immunosuppresion regimen (p < 0.06), use of biphosphonates (p < 0.73), presence of diabetes (p < 0.59), menopause in women (p < 0.08), season (p < 0.43) or race (p < 0.31). Our data indicate that 1,25-dihydroxyvitamin D metabolism remains disturbed for a considerable time after successful RT, with the result that the level of 1,25-dihydroxyvitamin D in RT patients is lower despite physiological signals that should stimulate its production. Our analysis of many clinical variables was unable to elucidate the underlying mechanism(s) for this disturbance., Conclusion: Successful RT may not produce appropriate levels of 1,25-dihydroxyvitamin D commensurate to the elevated levels of PTH. This abnormality along with sustained hyperparathyroidism may contribute to bone loss following transplantation.

Treatment of primary osteoporosis has advanced dramatically during the past decade, with more therapeutic options being available now than at any other time. Anti-resorptive (anti-catabolic) drugs have been prominent in the treatment of osteoporosis for decades. However, over time, several clinical observations made during use of these agents have challenged the prevailing dogma about mechanisms of drug action, changes in bone density and fracture reduction during treatment. It has become clear that changes in bone density are only a small part of the explanation for the dramatic reduction of fractures with treatment. From this paradox developed the notion of 'bone quality'- an operational term describing a number of characteristics that enable bone to resist fracturing. This article reviews this concept from a clinical perspective. It discusses the historical paradoxes found in clinical practice that have led to this notion, identifies the major areas of bone physiology circumscribed by the concept and focuses on present therapies and their effects on bone quality.

Objective: To determine the prevalence of low bone mass, fractures, and vitamin D deficiency and the levels of biochemical markers of mineral metabolism in patients with inflammatory bowel disease (IBD)., Methods: Our retrospective study consisted of 30 patients with Crohn's disease (CD) and 18 patients with ulcerative colitis (UC). Dual-energy x-ray absorptiometry was performed to determine bone mineral density at the lumbar spine and hip. Serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D (25-OHD), and 1,25-dihydroxyvitamin D, urinary N-telopeptide cross-linked collagen type I, and 24-hour urinary calcium levels were evaluated., Results: On the basis of Z-score definitions of low bone mass in the IBD group as a whole, 13 patients (27%) had low bone mass at the lumbar spine. Similarly, at the femoral neck, 13 patients (27%) had low bone mass. There was a higher prevalence of low bone mass in the UC group than in the CD group, consistent with a high prevalence of fractures in that group. Of all patients with IBD, 65% had a history of fractures, of which 23% were atraumatic. Deficiency of 25-OHD was high, with a prevalence of 55% in patients with UC and 83% in patients with CD. Secondary hyperparathyroidism, defined as a parathyroid hormone level >55 pg/mL in conjunction with a low or normal serum calcium and a low 25-OHD level, was present in 50% of patients with CD and only 7% of patients with UC., Conclusion: Metabolic bone disease and fractures are common in IBD. The mean bone mineral density of the spine or femoral neck did not differ significantly between patients with CD and those with UC. Patients with UC had a higher prevalence of low bone mass, as defined by a Z-score of less than -2, than did patients with CD, consistent with a high prevalence of fractures in the UC group. In contrast, hyperparathyroidism attributable to vitamin D deficiency was more prevalent in patients with CD than in those with UC. This finding suggests a different etiologic mechanism of low bone mass in patients with CD.

Introduction: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk., Methods: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX)., Results: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk., Conclusion: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

Although densitometry has contributed immensely to detecting primary osteoporosis, it is only a tool that generates some useful numbers to guide diagnosis. The T score, a leading diagnostic marker for primary osteoporosis, must be put in its proper context. It is but one measurement that is quite useful in one cohort of patients, namely, postmenopausal women older than 60, but it can be misleading in others. The z score is a more descriptive measurement of bone loss in younger patients. However, both the T score and z score are limited in their diagnostic potential and must be incorporated with other diagnostic aspects, such as family history, laboratory results, and genetic influences. In the end, physicians diagnose osteoporosis, not densitometry.

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Unlabelled: The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis., Introduction: Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD. We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD., Materials and Methods: In the Fracture Prevention Trial, 1637 postmenopausal women with osteoporosis were randomized to receive daily, self-administered, subcutaneous injections of placebo, teriparatide 20 microg/day, or teriparatide 40 microg/day. Serum concentrations of two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and the carboxy-terminal extension peptide of procollagen type 1 [PICP]) and urinary concentrations of two bone resorption markers (free deoxypyridinoline [DPD] and N-terminal telopeptide [NTX]) were assessed in a trial population subset (n = 520) at baseline and at 1, 3, 6, and 12 months. We also assessed serum concentrations of another bone formation marker, the amino-terminal extension peptide of procollagen type 1 (PINP), in a subset of 771 women at baseline and 3 months. Lumbar spine (LS) BMD was measured by DXA at baseline and 18 months. Femoral neck BMD was measured at baseline and 12 months., Results and Conclusion: Baseline bone turnover status correlated positively and significantly with BMD response. The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day. Among all studied biochemical markers, increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months (0.65 and 0.61, respectively; p < 0.05). The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response. Using receiver operator curve analysis, we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response.

Objective: To describe two clinical cases of systemic side effects from use of fluticasone nasal spray., Methods: A retrospective review of medical records of two patients using this drug was undertaken, and their clinical presentations and laboratory data are summarized., Results: Despite many clinical reports about the potential side effects from inhaled corticosteroids, no previously published clinical reports or studies have addressed such problems with the use of potent glucocorticoid nasal sprays. Two patients are described in whom different clinical problems developed after overuse of fluticasone nasal spray, a commonly advertised and prescribed drug. One patient was admitted to the hospital with symptoms of adrenal insufficiency. In the other patient, bone mineral density decreased substantially in 1 to 2 years despite preventive estrogen therapy. These patients had suppressed plasma or urinary cortisol, a low plasma adrenocorticotropic hormone (corticotropin) level, or an abnormal response to a cosyntropin stimulation test., Conclusion: Patients should be clearly warned that the prescribed dosing for fluticasone nasal spray should be carefully followed because overuse may cause serious side effects.

Objective: To review the literature concerning the history, development, and therapeutic uses of bisphosphonates., Data Sources: English-language articles were identified through a search of MEDLINE (through December 2004) using the key word bisphosphonate. Reference lists of pivotal studies, reviews, and full prescribing information for the approved agents were also examined., Study Selection and Data Extraction: Selected studies included those that discussed the discovery and initial applications of bisphosphonates, as well as their historical development, pharmacokinetic and pharmacodynamic properties, and current therapeutic uses., Data Synthesis: Bisphosphonates structurally resemble pyrophosphates (naturally occurring polyphosphates) and have demonstrated similar physicochemical effects to pyrophosphates. In addition, bisphosphonates reduce bone turnover and resist hydrolysis when administered orally. The information gained from initial work with etidronate generated a considerable scientific effort to design new and more effective bisphosphonates. The PCP moiety in the general bisphosphonate structure is essential for binding to hydroxyapatite and allows for a number of chemical variations by changing the 2 lateral side chains (designated R(1) and R(2)). The R(1) side chain determines binding affinity to hydroxyapatite, and the R(2) side chain determines antiresorptive potency. Accordingly, each bisphosphonate has its own characteristic profile of activity., Conclusions: The bisphosphonates reduce bone turnover, increase bone mass, and decrease fracture risk and therefore have a significant place in the management of skeletal disorders including osteoporosis, Paget's disease, bone metastases, osteogenesis imperfecta, and heterotopic ossification.

Objective: To determine whether hip fracture patients, a group at very high risk for additional fragility fractures, are being evaluated and treated effectively for osteoporosis., Methods: Clinical and bone densitometry (dual x-ray absorptiometry [DXA]) records were reviewed in hip fracture patients at 4 Midwestern US health systems to determine the frequency of DXA use, calcium and vitamin D supplementation, and antiresorptive drug treatment., Results: DXA was performed at the 4 study sites in only 12%, 12%, 13%, and 24% of patients, respectively. Calcium and vitamin D supplements were prescribed in 27%, 1%, 3%, and 25% of the patients at the 4 study sites. Antiresorptive drugs were prescribed in 26%, 12%, 7%, and 37% of the patients with only 2-10% receiving a bisphosphonate., Conclusion: Reducing osteoporotic fractures will require more effective approaches to managing hip fracture patients and other high-risk populations.

Alendronate and risedronate, the two oral bisphosphonates approved in the United States for preventing and treating osteoporosis, have never been compared in direct head-to-head trials, but they appear to have similar pharmacokinetics, drug interactions, adverse effect profiles, and efficacy. Alendronate, however, can be given as a once-weekly dose, whereas risedronate is not yet available in this dosage form. On the other hand, alendronate is not approved for preventing glucocorticoid-induced osteoporosis, whereas risedronate carries this indication.

Bisphosphonates are effective treatments for osteoporosis, but some have been associated with upper gastrointestinal intolerance. This randomized, double-blind study assessed the upper gastrointestinal tolerability of risedronate in postmenopausal women who had discontinued alendronate treatment because of upper gastrointestinal adverse events. Sixty-six women who had previously discontinued treatment with alendronate 10 mg/day because of upper gastrointestinal symptoms received placebo (N=31) or risedronate 5 mg (N=35) daily for 3 months. The primary outcome was the rate of discontinuation due to upper gastrointestinal adverse events: 5/31 (16.1%) in the placebo group, and 4/35 (11.4%) in the risedronate group. Discontinuation rates were also similar in the two treatment groups among subgroups of patients with a history of gastrointestinal disorder, prior use of acid suppression drugs, and concomitant use of NSAIDs. The overall incidence of upper gastrointestinal events was comparable between the placebo (19.4%) and risedronate (20.0%) groups. Overall, risedronate 5 mg/day for 3 months was as well tolerated as placebo in patients who could not tolerate alendronate 10 mg. These results are consistent with, and complement those from previous studies showing that risedronate 5 mg has a gastrointestinal tolerability similar to that of placebo.

Quantitative ultrasound (QUS) is receiving considerable attention in the assessment of osteoporosis because of its ease of use, lack of radiation exposure, region of interest, and relatively low costs. These features have made the technique appealing for screening adult and pediatric patients. This article discusses some of the clinical applications, limitations, and strengths of QUS.

Background: There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been > or =30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients., Objective: To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo., Methods: This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8., Results: A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences., Conclusion: The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Selective estrogen receptor modulators (SERMs) are a new class of drugs that provide a new option for addressing the health challenges of postmenopausal women. This review discusses the proposed mechanism of action of SERMs and describes clinical findings on raloxifene, a SERM now available for treating and preventing osteoporosis.

Osteoporosis and Paget's disease of bone are the most common metabolic bone diseases. They cause considerable disability and pain, and reduce quality of life. The elderly are at greatest risk of osteoporotic fractures, and in an ageing world population, the burden of the disease is likely to increase. Bisphosphonates are known to be effective antiresorptive agents for the treatment of Paget's disease of bone, postmenopausal osteoporosis (PMO) and corticosteroid-induced osteoporosis (CIO). However, some bisphosphonates have been associated with troublesome gastrointestinal side-effects. Risedronate is a novel pyridinyl bisphosphonate recently approved in the USA for the treatment of Paget's disease, and is under development for the treatment of PMO and CIO. Risedronate is effective and well-tolerated in the treatment of Paget's disease. It has the shortest treatment regimen of any oral bisphosphonate; a two month course of therapy results in sustained remission, as determined by biochemical indices. The results of recent clinical trials suggest that risedronate is also an effective, well-tolerated therapy for PMO and CIO. Risedronate represents an advance in the therapeutic options available for the treatment of Paget's disease, and is expected to be of further value for treatment of PMO and CIO when it receives approval for use in these conditions.

Purpose: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy., Patients and Methods: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs., Results: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures., Conclusions: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

The bisphosphonates are long-lived synthetic analogs of pyrophosphate, a natural, short-lived inhibitor of bone. Oral doses share similar qualities (ie, they inhibit bone resorption, poor absorption, and potential gastrointestinal irritants), but each one has a unique spectrum of potency and a probable mechanism of action. The parent compound, etidronate, was first used in multicentered trials for the treatment of primary osteoporosis and showed some success in increasing bone density and perhaps controlling fracture rates. The recently approved drug alendronate is a more potent agent than etidronate, produces a greater increase in bone density, and decreases fractures. Oral and intravenous pamidronate have similar positive effects on bone density. Studies with tiludronate, risedronate, and clodronate show similar promise as therapeutic agents.

Purpose: To review the literature on the effects of amiodarone on thyroid physiology and management of amiodarone-induced thyroid disease., Data Sources: English-language articles identified through a MEDLINE search (for 1975 to 1995, using the terms amiodarone and thyroid) and selected cross-referenced articles., Study Selection: Articles on the effects of amiodarone on thyroid physiology and function tests and occurrence, recognition, and management of amiodarone-induced thyroid disease., Data Extraction: Data were manually extracted from selected studies and reports; emphasis was placed on information relevant to the practicing clinician., Data Synthesis: Amiodarone can have many effects on thyroid function test results, even in the absence of hyperthyroidism or hypothyroidism. It may cause an increase in serum levels of thyroxine, reverse triiodothyronine, and thyroid-stimulating hormone and a decrease in serum triiodothyronine levels. Thyrotoxicosis occurs in some patients and is related to several pathogenetic mechanisms. It often present dramatically with obvious clinical manifestations and further changes in thyroid function test results. Medical options include therapy with thionamides, perchlorate, and prednisone. Radioactive iodine is of little use. Thyroidectomy is effective and is the only measure that consistently allows continued use of amiodarone. Unlike thyrotoxicosis, hypothyroidism is related to a persistent Wolff-Chaikoff effect and often has a vague presentation. The goal of treatment of amiodarone-induced hypothyroidism is to bring serum thyroxine levels to the upper end of the normal range, as often seen in euthyroid patients who are receiving amiodarone., Conclusions: Thyroid dysfunction commonly occurs with amiodarone therapy. It may be difficult to recognize the dysfunction because of the many changes in thyroid function test results that occur in euthyroid patients who are receiving amiodarone. Effective strategies exist for the management of hyperthyroidism and hypothyroidism; these should be tailored to the needs of the individual patient.

Purpose: The use of preoperative imaging studies in patients with persistent or recurrent hyperparathyroidism after initial operation is generally accepted to improve the success rate and minimize the morbidity from reoperative surgery. The purpose of this study was to define the performance of FDG-PET for the localization of hyperfunctioning parathyroid tissue prior to reoperation., Method: Twenty patients with biochemical evidence of recurrent or persistent hyperparathyroidism following previous neck surgery were investigated. Regional body PET imaging of the neck and upper chest (axial field of view 27.5 cm) was acquired 45 min after 5-10 mCi FDG was given intravenously., Results: Subsequent surgery revealed solitary parathyroid adenomas in 14 patients, seven hyperplastic glands in 2 patients, and parathyroid carcinoma in 1 patients. FDG-PET correctly identified 79% (11/14) of the parathyroid adenomas, 29% (2/7) of the hyperplastic glands, and the parathyroid carcinoma. FDG-PET was negative in 79% (30/38) of the surgically identified normal parathyroid glands. Eight false-positive findings led to a positive predictive value of 64%., Conclusion: These preliminary data suggest that regional body FDG-PET is a promising procedure in the evaluation of patients with persistent or recurrent postoperative hyperparathyroidism.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

To delineate the incidence, clinical features, diagnosis, and treatment options for amiodarone induced hyperthyroidism (AIH), we reviewed the medical records of ten patients with AIH. Eight of these 10 patients were detected on initial review of the records of 200 patients in treatment with amiodarone, and the other 2 following notification by their endocrinologists. AIH occurred in 4.2% of patients being treated with amiodarone. At the time of diagnosis of AIH, the mean (SD) values for age, duration of treatment with amiodarone, and dose of amiodarone were 62.9 (8.96) years, 38.3 (20) months, and 366.7 (122) mg/day, respectively. The most common clinical features were weight loss and goiter (each seen in 90% of patients). Serum thyroxine (T4), triiodothyronine, and free thyroxine index (FTI) showed an increase of 84%, 47%, and 110%, while thyroid stimulating hormone (TSH) and resin T4 uptake decreased 96% and 14%, respectively, from previous values. The most consistent laboratory findings, seen in all patients, were subnormal TSH and abnormally high FTI. One patient required no treatment; another underwent prompt total thyroidectomy. The other eight were treated medically; two of them underwent total thyroidectomy later, for medical failure or adverse effects. Amiodarone was continued in four patients. The most commonly used antithyroid medication was propylthiouracil. AIH presents in the early or late phases of treatment with amiodarone with typical clinical features of a hyperthyroid state, fall in TSH, and increase in FTI. Antithyroid medications are reasonably effective in the management of AIH.

Unlabelled: Preoperative localization of hyperfunctioning parathyroid tissue in patients with primary hyperparathyroidism has been a longstanding diagnostic challenge. This study directly compared FDG-PET and sestamibi-SPECT for preoperative detection of abnormal parathyroid tissue., Methods: Twenty-one consecutive patients with primary hyperparathyroidism were studied prospectively before surgical neck exploration. SPECT of the neck and chest was performed at 15 min and 2 hr after intravenous 99mTc-sestamibi. Regional body PET was performed 45 min after intravenous FDG., Results: Surgery revealed 19 solitary parathyroid adenomas, 2 parathyroid adenomas in one patient; and 3 hyperplastic parathyroid glands in one patient, and 51 normal parathyroid glands. The diagnostic sensitivities for detection of parathyroid adenomas of 43% (9 of 21) for dual-phase sestamibi-SPECT and 86% (18 of 21) for FDG-PET were significantly different (p < 0.001). The difference in diagnostic specificities of 78% (40 of 51) for FDG-PET and 90% (46 of 51) for dual-phase sestamibi-SPECT approached statistical significance (p = 0.063)., Conclusion: This study demonstrates that FDG-PET is more sensitive than sestamibi-SPECT in the preoperative localization of parathyroid adenomas in patients with primary hyperparathyroidism.

Background: Primary osteoporosis affects one in four women over the age of 65 and reflects lifelong processes and trends., Summary: Skeletal bone constantly repairs the microscopic damage it sustains as a result of the normal activities of living. Women achieve their maximum bone density by the close of adolescence. Hereditary, nutritional, hormonal, and life-style factors affect the process of osteoporosis. Bone densitometry can detect very small deficits long before losses become clinically apparent. Intervention can halt osteoporosis at any point and perhaps increase bone density, but no known therapy can restore the normal bone architecture once it is lost., Key Points: Women should maintain an adequate intake of calcium throughout their lifetime, especially during adolescence. Bone densitometry at the time of menopause detects preclinical osteoporosis and enables physicians to start therapy to preserve the bone structure.