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Krege J.H.,Lilly United States | Lane N.E.,University of California at Davis | Harris J.M.,Eli Lilly and Company | Miller P.D.,University of Colorado at Denver | Miller P.D.,Colorado Center for Bone Research
Osteoporosis International | Year: 2014

Postmenopausal women with severe osteoporosis may require treatment with the bone anabolic drug teriparatide. While changes in bone mineral density (BMD) are one measure of response, BMD changes often require a minimum of one year to observe measureable changes. Biochemical markers of bone turnover change within 1 to 3 months of initiating osteoporosis therapy. Monitoring with a marker such as procollagen type I N propeptide (PINP), an osteoblast-derived protein, during teriparatide treatment may provide clinically useful information for managing patients with osteoporosis. Clinical trials have shown consistent increases in PINP within 3 months of initiating teriparatide, increases that are significantly greater than placebo and significantly different from baseline. Increases in PINP concentrations during teriparatide treatment correlate well with increases in skeletal activity assessed by radioisotope bone scans and quantitative bone histomorphometry parameters. Individuals treated with teriparatide in clinical trials usually experienced an increase in PINP > 10 mcg/L from baseline, while those given placebo usually did not. In the clinical setting, patients experiencing a significant increase in PINP > 10 mcg/L after initiating teriparatide therapy may receive an earlier confirmation of anabolic effect, while those who do not may be assessed for adherence, proper injection technique, or undetected secondary conditions that might mitigate an anabolic response. PINP monitoring may provide information supplemental to BMD monitoring and be a useful aid in managing patients receiving anabolic osteoporosis treatment in the same way that biochemical markers of bone resorption are useful in monitoring antiresorptive therapy. This review examines PINP as a biological response marker during teriparatide treatment for osteoporosis. © 2014 The Author(s).

Lewiecki E.M.,New Mexico Clinical Research and Osteoporosis Center | Miller P.D.,Colorado Center for Bone Research
Journal of Clinical Densitometry | Year: 2013

Parathyroid hormone (PTH) is associated with anabolic and catabolic skeletal effects that vary according to the kinetics of serum levels and the type of bone. The anabolic effects are manifested in patients with a periodic rapid transient rise in serum PTH, as seen with daily subcutaneous injection of PTH(1-34) and PTH(1-84) in the treatment of osteoporosis. These patients have an increase in bone mineral density (BMD), particularly at skeletal sites with a high trabecular component, such as the lumbar spine, and a reduction in fracture risk. The catabolic effects are typified in patients with primary hyperparathyroidism (PHPT) who have chronic persistently elevated PTH levels. Patients with long-standing PHPT have a reduction in BMD, particularly at predominately cortical skeletal sites, such as the one-third radius, with relative preservation of BMD at the lumbar spine. Some but not all studies have reported an increase in fracture risk with PHPT. Because many patients with PHPT are postmenopausal women at risk for osteoporosis owing to estrogen deficiency, BMD and fracture risk may be a result of multiple factors with variable effects on bone remodeling. The skeletal effects of normocalcemic PHPT have not yet been fully characterized, but may not be the same as hypercalcemic PHPT. © 2013 The International Society for Clinical Densitometry.

Miller P.D.,Colorado Center for Bone Research
Journal of Clinical Densitometry | Year: 2016

Vertebral compression fractures (VCF's) are the most common form of osteoporotic fractures. Whether symptomatic or asymptomatic, they both represent a high risk for not only vertebral but also nonvertebral fractures in untreated populations. This high risk of future fracture after a VCF is independent of the T-score because bone strength is a combination of bone mineral density and bone quality. VCFs are the single greatest risk for future fractures at all other skeletal sites in untreated populations, including hip fractures. They are often unrecognized despite their exceptionally high prevalence in all genders and most ethnic groups as age increases. This article highlights some of the key messages about VCF's, and how assessment for their presence and then management will reduce the risk of all osteoporotic fractures. © 2016 The International Society for Clinical Densitometry.

Miller P.D.,Colorado Center for Bone Research
Journal of Clinical Endocrinology and Metabolism | Year: 2016

Context: An expert opinion perspective on why osteoporosis is underdiagnosed and undertreated. Objective: To highlight the potential reasons for why osteoporosis is undertreated. Design: Literature review from PubMed, Plos One, and Science Direct search engines from 1900-2015 under terms: sub-trochanteric and atypical femur fractures, bisphosphonate clinical trial and bisphosphonate review articles, and treatment/under treatment of osteoporosis, as well as personal experience. Setting: Careful and objective review. Patients: Derived from reviews. Interventions: Bisphosphonates. Outcomes: Atypical sub-trochanteric femur fractures. Results: Atypical sub-trochanteric femur fractures occur in both bisphosphonate and non-bisphosphonate users; and, bisphosphonate utilization has declined in temporal relationship with the reporting of these fractures associated with bisphosphonate use. There is no causality in this association and the benefit/risk ratio of bisphosphonates reducing all fracture risk vs the potential for the development of an atypical sub-trochanteric femur fracture is exceedingly in favor of bisphosphonate use in higher risk populations. Conclusions: Treatments for osteoporosis should not be stopped (e.g. The "drug-holidays") in higher risk patients since the basic pathophysiology of osteoporosis continues; and, the evidence linking bisphosphonate use to causing atypical sub-trochanteric femur fractures is non-existent. © 2016 by the Endocrine Society.

Jamal S.A.,University of Toronto | Jamal S.A.,Womens College Research Institute | West S.L.,University of Toronto | West S.L.,Womens College Research Institute | Miller P.D.,Colorado Center for Bone Research
Osteoporosis International | Year: 2012

Fractures are common in patients with chronic kidney disease (CKD) and associated with substantially high morbidity and mortality. Bone mass measurements are commonly used to assess fracture risk in the general population, but the utility of these measurements in patients with CKD, and specifically among those on hemodialysis, is unclear. This review will outline the epidemiology and etiology of fractures in patients with CKD with a particular emphasis on men and women on hemodialysis. As well, we will summarize the published data, which describes the association between risk factors for fracture (including bone mass measurements, biochemical markers of mineral metabolism, and muscle strength) and fractures in patients with CKD. Patients with CKD suffer from fractures due to impairments in bone quantity, bone quality, and abnormalities of neuromuscular function. There is a paucity of evidence on the associations between bone quality, bone turnover markers, neuromuscular function, and fractures in patients with CKD. Furthermore, the complex etiology of fractures combined with the technical limitations of bone mineral density testing, both by dual energy X-ray absorptiometry (DXA) and by peripheral quantitative tomography (pQCT), limits the clinical utility of bone mass measurements for fracture prediction in CKD; this is particularly true among patients with stages 4 and 5 CKD. Further prospective studies to identify noninvasive measures of bone strength that can be used for fracture risk assessment are needed. © The Author(s) 2011.

Miller P.D.,Colorado Center for Bone Research
Bone Research | Year: 2015

Fractures across the stages of chronic kidney disease (CKD) could be due to osteoporosis, some form of renal osteodystrophy defined by specific quantitative histomorphometry or chronic kidney disease-mineral and bone disorder (CKD-MBD). CKD-MBD is a systemic disease that links disorders of mineral and bone metabolism due to CKD to either one or all of the following: abnormalities of calcium, phosphorus, parathyroid hormone or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth or strength; or vascular or other soft-tissue calcification. Osteoporosis, as defined by the National Institutes of Health, may coexist with renal osteodystrophy or CKD-MBD. Differentiation among these disorders is required to manage correctly the correct disorder to reduce the risk of fractures. While the World Health Organization (WHO) bone mineral density (BMD) criteria for osteoporosis can be used in patients with stages 1-3 CKD, the disorders of bone turnover become so aberrant by stages 4 and 5 CKD that neither the WHO criteria nor the occurrence of a fragility fracture can be used for the diagnosis of osteoporosis. The diagnosis of osteoporosis in stages 4 and 5 CKD is one of the exclusion - excluding either renal osteodystrophy or CKD-MBD as the cause of low BMD or fragility fractures. Differentiations among the disorders of renal osteodystrophy, CKD-MBD or osteoporosis are dependent on the measurement of specific biochemical markers, including serum parathyroid hormone (PTH) and/or quantitative bone histomorphometry. Management of fractures in stages 1-3 CKD does not differ in persons with or without CKD with osteoporosis assuming that there is no evidence for CKD-MBD, clinically suspected by elevated PTH, hyperphosphatemia or fibroblast growth factor 23 due to CKD. Treatment of fractures in persons with osteoporosis and stages 4 and 5 CKD is not evidence-based, with the exception of post-hoc analysis suggesting efficacy and safety of specific osteoporosis therapies (alendronate, risedronate and denosumab) in stage 4 CKD. This review also discusses how to diagnose and manage fragility fractures across the five stages of CKD. © 2014 Sichuan University All rights reserved.

Jamal S.A.,University of Toronto | Miller P.D.,Colorado Center for Bone Research
Journal of Clinical Densitometry | Year: 2013

We reviewed the etiology and management of secondary and tertiary hyperparathyroidism. Secondary hyperparathyroidism is characterized by an increase in parathyroid hormone (PTH) that is appropriate and in response to a stimulus, most commonly low serum calcium. In secondary hyperparathyroidism, the serum calcium is normal and the PTH level is elevated. Tertiary hyperparathyroidism is characterized by excessive secretion of PTH after longstanding secondary hyperparathyroidism, in which hypercalcemia has ensued. Tertiary hyperparathyroidism typically occurs in men and women with chronic kidney disease usually after kidney transplant. The etiology and treatment of secondary hyperparathyroidism is relatively straightforward whereas data on the management of tertiary hyperparathyroidism is limited to a few small trials with short follow-up. © 2013 The International Society for Clinical Densitometry.

Miller P.D.,Colorado Center for Bone Research | McCarthy E.F.,Johns Hopkins University
Seminars in Arthritis and Rheumatism | Year: 2015

Objectives: Bisphosphonate-associated atypical sub-trochanteric femur fractures (ASFF) may be seen with long-term bisphosphonate use, though these fractures are also seen in patients never exposed to bisphosphonates. One theory for the mechanism of action whereby bisphosphonates may induce these ASFF is over-suppression of bone turnover. Bisphosphonates suppress bone turnover, but in bisphosphonate clinical trials, over-suppression defined whether by maintaining the biochemical markers of bone turnover below the defined reference range or by quantitative bone histomorphometry, has not been observed. Methods: We studied 15 clinic patients referred to The Colorado Center for Bone Research (CCBR) after they had a bisphosphonate-associated ASFF and performed quantitative bone histomorphometry both before and after 12 months of teriparatide (20. μg SQ/day). All patients had been on long-term alendronate (mean = 7 years, range: 6-11 years) and had already had intramedullary rods placed when first seen (6 weeks to 7 months after rod placement). Alendronate had been discontinued in all patients at the time of their first clinic visit to CCBR. All of the fractures fulfilled The American Society for Bone and Mineral Research major radiological criteria for ASFF. Results: Three key dynamic histomorphometric features show that 7 of the 15 patients had unmeasurable bone formation, mineralizing surface, and mineral apposition, while the other 8 patients had measurable dynamic parameters; although for all 15 patients, the mean values for all 3 dynamic parameters was far below the average for the published normal population. Administration of teriparatide was associated with an increase in all 3 dynamic histomorphometric parameters. Baseline bone turnover markers did not correlate with the baseline histomorphometry. While there is heterogeneity in the bone turnover in patients with bisphosphonate ASFF, there is a large portion in this uncontrolled series that had absent bone turnover at the standard biopsy site (iliac crest). Discontinuation of the bisphosphonate and administration of the anabolic agent, teriparatide was associated with improvement in bone turnover. Conclusions: While our study does not establish causality or address the ability of teriparatide to prevent progression of early stress fracture to displaced fractures, it does suggest that teriparatide may improve bone formation in these patients. Our study should stimulate other investigations using larger sample sizes and early stress fractures to see if anabolic agents can reverse these fractures from becoming displaced. © 2014 Elsevier Inc.

Miller P.D.,Colorado Center for Bone Research
Endocrinology and Metabolism Clinics of North America | Year: 2012

There are a substantial number of secondary causes of osteoporosis that can be identified through appropriate evaluation. Unrecognized celiac disease, Monoclonal gamopathy of undetermined significance (MGUS), impaired renal function, diabetes mellitus, and renal tubular acidosis are just a few of the more common secondary causes of osteoporosis. Through targeted laboratory tests, many secondary causes of osteoporosis can be identified. © 2012.

Bone H.G.,Michigan Bone and Mineral Clinic | Bolognese M.A.,Bethesda Health Research Center | Yuen C.K.,University of Manitoba | Kendler D.L.,Clinical Research Center | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. Objective: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. Design: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel- group study. Participants: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of ≤1.61 at randomization participated in the study. Interventions: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. Main Outcome Measures: We measured the percentage changes in BMD and BTM, and evaluated safety. Results: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%),comparedwith placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P= 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. Conclusions: In postmenopausalwomenwith lowBMD,the effects of 60mgdenosumabtreatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo. Copyright © 2011 by The Endocrine Society.

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