Paget's disease of bone: an endocrine society clinical practice guideline

OBJECTIVE: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone. PARTICIPANTS: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. CONCLUSIONS: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.(AU)

Bisphosphonates in Paget's disease.

Paget's disease is the best example of a common high turnover bone disease. A review of the early use of bisphosphonates in the treatment of this condition shows that many of the fundamental therapeutic issues were identified using drugs which by today's standards were far from ideal. Over the succeeding decades there has been a steady increase in potency culminating in the introduction of intravenous zoledronic acid which is capable of inducing long term remissions which were unthinkable when bisphosphonates were first introduced.

Vitamin D status in renal transplant recipients.

Vitamin D plays an important role in calcium homeostasis. Renal transplant recipients may be more susceptible to reduced levels because of decreased sun exposure and steroid therapy. This study aimed to determine vitamin D status after renal transplantation and its effect on parathyroid hormone (PTH) and bone mineral density (BMD). We measured serum 25-hydroxyvitamin D levels (25-OHD) in 244 renal transplant recipients, divided into two groups, 104 recently transplanted (less than 1 year) and 140 long-term. Vitamin D status was defined according to NKF/KDOQI guidelines. Mean 25-OHD levels were 33 +/- 19 nmol/L and 42 +/- 20 nmol/L, respectively, for the recent and long-term transplant recipients. Vitamin D insufficiency was present in 29% and 43%, deficiency in 56% and 46% and severe deficiency in 12% and 5%, respectively. An inverse correlation was found between logPTH and 25-OHD (r=-0.2, p= 0.019) in long-term but not in recently transplanted patients. No correlation was found between 25-OHD levels and BMD. Hypercalcaemia was present in 40% of the recently transplanted recipients and 25% of the long-term. In conclusion 25-OHD was low in virtually all of our renal transplant recipients and may aggravate secondary hyperparathyroidism, but its correction may be difficult in patients with hypercalcaemia.

Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency.

INTRODUCTION: Vitamin D insufficiency is common, however within individuals, not all manifest the biochemical effects of PTH excess. This further extends to patients with established osteoporosis. The mechanism underlying the blunted PTH response is unclear but may be related to magnesium (Mg) deficiency. The aims of this study were to compare in patients with established osteoporosis and differing degrees of vitamin D and PTH status : (1) the presence of Mg deficiency using the standard Mg loading test (2) evaluate the effects of Mg loading on the calcium-PTH endocrine axis (3) determine the effects of oral, short term Mg supplementation on the calcium-PTH endocrine axis and bone turnover. METHODS: 30 patients (10 women in 3 groups) were evaluated prospectively measuring calcium, PTH, Mg retention (Mg loading test), dietary nutrient intake (calcium, vitamin D, Mg) and bone turnover markers (serum CTX & P1CP). Multivariate analysis controlling for potential confounding baseline variable was undertaken for the measured outcomes. RESULTS: All subjects, within the low vitamin D and low PTH group following the magnesium loading test had evidence of Mg depletion [mean(SD) retention 70.3%(12.5)] and showed an increase in calcium 0.06(0.01) mmol/l [95% CI 0.03, 0.09, p=0.007], together with a rise in PTH 13.3 ng/l (4.5) [95% CI 3.2, 23.4, p=0.016] compared to baseline. Following oral supplementation bone turnover increased: CTX 0.16 (0.06) mcg/l [95%CI 0.01, 0.32 p=0.047]; P1CP 13.1 (5.7) mcg/l [95% CI 0.29, 26.6 p=0.049]. In subjects with a low vitamin D and raised PTH mean retention was 55.9%(14.8) and in the vitamin replete group 36.1%(14.4), with little change in both acute markers of calcium homeostasis and bone turnover markers following both the loading test and oral supplementation. CONCLUSIONS: This study confirms that in patients with established osteoporosis, there is also a distinct group with a low vitamin D and a blunted PTH level and that Mg deficiency (as measured by the Mg loading test) is an important contributing factor.

Alendronate sodium in the management of osteoporosis.

Alendronate is one of the best and most extensively studied bisphosphonates in the treatment of osteoporosis. This review considers in detail the major pivotal study, the fracture intervention trial (FIT), upon which the use of alendronate is based and which was a landmark study in terms of design, size and clinical impact. The role of alendronate has subsequently been underscored by a range of studies extending the clinical indications for its use and consolidating the effect on reducing both vertebral and non-vertebral fracture risk. Although the emphasis of these studies has predominantly been on the management of postmenopausal osteoporosis, data is also available in primary prevention, men, and glucocorticoids-induced osteoporosis. Direct comparison between the different drugs used to treat osteoporosis with fracture end points are needed for patients and doctors to make informed choices, but the size of such studies are prohibitive. Clinical trials using surrogate markers such as bone mineral density and biochemical markers of bone turnover have been performed which provide some helpful information but the limitations of this approach need to be recognized.

Osteoporosis therapy: an example of putting evidence-based medicine into clinical practice.

A major aim of evidence-based medicine is to assist clinical decision-making by providing the most current and reliable medical information. Systematic reviews and meta-analyses are important tools in this process. Systematic reviews identify and compile relevant evidence, while meta-analyses summarize and quantify the results of such reviews. Results from meta-analyses are, at present, the main source of summary evidence for the efficacy of treatments for a specific condition. They are important tools for helping to choose among treatment options, although they cannot be used to directly compare the magnitude of the effect of various therapies. However, the methods used and the consequent clinical value of the results, may be poorly understood by clinicians, who may therefore not take full advantage of the evidence. Recently, a panel of experts in osteoporosis and evidence-based medicine applied rigorous, validated, scientific standards to produce a systematic review and meta-analysis of randomized controlled trials of anti-resorptive agents used to treat osteoporosis. They found that, although several agents reduced the risk of vertebral fracture, only two, alendronate and risedronate, demonstrated convincing evidence for both non-vertebral and vertebral fracture risk reductions. The clinical implication of these results is that there are important differences in anti-fracture efficacy among currently available agents. In the absence of evidence from head-to-head clinical trials and because of the systematic nature and methodological rigor of the analyses, these data provide important information for clinical decision-making.

The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis.

It is evident from several studies that not all patients with hypovitaminosis D develop secondary hyperparathyroidism. What this means for bone biochemistry and bone mineral density (BMD) remains unclear. The aim of this study was to investigate the effects of hypovitaminosis D (defined as a 25OHD < or = 30 nmol/l) and patients with a blunted PTH response (defined arbitrarily as a PTH within the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) in comparison to patients with hypovitaminosis D and secondary hyperparathyroidism (defined arbitrarily as a PTH above the standard laboratory reference range in the presence of a 25OHD < or = 30 nmol/l) and vitamin D-replete subjects (25OHD > 30 nmol/l). Four hundred twenty-one postmenopausal women (mean age: 71.2 years) with established vertebral osteoporosis were evaluated by assessing mean serum calcium, 25OHD, 1,25(OH)2D, bone turnover markers, and BMD. The prevalence of hypovitaminosis D was 39%. Secondary hyperparathyroidism was found in only one-third of these patients who maintained calcium homeostasis at the expense of increased bone turnover relative to the vitamin D-replete subjects (bone ALP mean difference: 43.9 IU/l [95% CI: 24.8, 59.1], osteocalcin: 1.3 ng/ml [95% CI: 1.1, 2.5], free deoxypyridinoline mean difference: 2.6 nmol/nmol creatinine [95% CI: 2.5, 4.8]) and bone loss (total hip BMD mean difference: 0.11 g/cm2 [95% CI: 0.09, 0.12]). Patients with hypovitaminosis D and a blunted PTH response were characterized by a lower serum calcium (mean difference: 0.07 mmol/l [95% CI: 0.08, 0.2]), a reduction in bone turnover (bone ALP mean difference: 42.4 IU/l [95% CI: 27.8, 61.9], osteocalcin: 1.6 ng/ml [95% CI: 0.3, 3.1], free-deoxypyridinoline mean difference: 3.0 nmol/nmol creatinine [95% CI: 1.9, 5.9]), but protection in bone density (total hip BMD mean difference: 0.10 g/cm2, [95% CI: 0.08, 0.11]) as compared to those with hypovitaminosis D and secondary hyperparathyroidism. This study identifies a distinct group of patients with hypovitaminosis D and a blunted PTH response who show a disruption in calcium homeostasis but protected against PTH-mediated bone loss. This has clinical implications with respect to disease definition and may be important in deciding the optimal replacement therapy in patients with hypovitaminosis D but a blunted PTH response.

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience.

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% (P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.

Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.

We investigated the effect of alendronate on calcium, PTH, and bone mineral density in 27 female and 5 male patients with primary hyperparathyroidism. The treatment group [n = 14; T score < or = -2.5 SD at the femoral neck (FN) or T < or = -1.0 SD plus previous nonvertebral fracture] was given alendronate 10 mg/d for 24 months. The second group (n = 18; T score > -2.5 SD at the FN) was untreated. Biochemistry was repeated at 1.5, 3, 6, 12, 18, and 24 months, and dual-energy x-ray absorptiometry at 12 and 24 months. There were no significant between-group baseline differences in calcium, creatinine, or PTH. Alendronate-treated patients gained bone at all sites [lumbar spine (LS), 1 yr gain, +7.3 +/- 1.7%; P < 0.001; 2 yr, +7.3 +/- 3.1%; P = 0.04). Untreated patients gained bone at the LS over 2 yr (+4.0 +/- 1.8%; P = 0.03) but lost bone elsewhere. Calcium fell nonsignificantly in the alendronate group between baseline (2.84 +/- 0.12 mmol/liter) and 6 wk (2.76 +/- 0.09 mmol/liter), with a nonsignificant rise in PTH (baseline, 103.5 +/- 14.6 ng/liter; 6 wk, 116.7 +/- 15.6 ng/liter). By 3 months, values had reverted to baseline. In primary hyperparathyroidism, alendronate is well tolerated and significantly improves bone mineral density at the LS (with lesser gains at FN and radius), especially within the first year of treatment. Short-term changes in calcium and PTH resolve by 3 months.

Management of corticosteroid-induced osteoporosis.

Corticosteroid (CS) therapy is widely used in the treatment of rheumatic diseases. Osteoporosis remains one of its major complications. The risk of low bone mineral density (BMD) and fracture may be already increased in some of the rheumatic diseases, regardless of CS therapy. However, in spite of this, preventative treatment for osteoporosis in patients on CS remains low. Patients on or about to start CS use for more than 6 months are at risk of corticosteroid-induced osteoporosis (CIOP). The pathogenesis of CIOP differs from post-menopausal osteoporosis in that bone formation is said to be more suppressed compared with bone resorption. The diagnosis of CIOP can be made on clinical risk factors and may not require measurement of BMD. Many agents used in post-menopausal osteoporosis such as activated vitamin D products, hormone replacement therapy, fluoride, calcitonin and the bisphosphonates have been shown to maintain or improve BMD in CIOP. However, there are few data on the reduction in fracture rates in CIOP, but the bisphosphonates seem the most promising in this regard.

The management of primary hyperparathyroidism.

Recent improvements in parathyroid imaging have led to renewed interest in the criteria for, and the surgical approach to, parathyroidectomy. It therefore seemed appropriate to review current evidence relating to the evaluation and management of primary hyperparathyroidism for those working within a general endocrine service. The recommendations are based on an electronic search spanning the past decade using the search terms hyperparathyroidism, management and parathyroidectomy/surgery, but we have also included key publications outside this period. The findings have been graded systematically (Appendix), according to the quality of the information available, to indicate the level of evidence on which they are based.

Hypovitaminosis D and 'functional hypoparathyroidism'-the NoNoF (Nottingham Neck of Femur) study.

BACKGROUND: calcium and vitamin D deficiency are common in elderly people and lead to increased bone loss, with an enhanced risk of osteoporotic fractures. Although hip fractures are a serious consequence, few therapeutic measures are given for primary or secondary prevention. A combination of calcium and vitamin D may not be the most effective treatment for all patients. OBJECTIVE: to investigate the effects of hypovitaminosis D on the calcium-parathyroid hormone endocrine axis, bone mineral density and fracture type, and the optimal role of combination calcium and vitamin D therapy after hip fracture in elderly patients. DESIGN: a population-based, prospective cohort study. METHODS: 150 elderly subjects were recruited from the fast-track orthogeriatric rehabilitation ward within 7 days of surgery for hip fracture. This ward accepts people who live at home and are independent in activities of daily living. All subjects had a baseline medical examination, biochemical tests (parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) and were referred for bone densitometry. RESULTS: at 68%, the prevalence of hypovitaminosis D (25-hydroxyvitamin D<30 nmol/l) was high. However, only half the patients had evidence of secondary hyperparathyroidism, the rest having a low to normal level of parathyroid hormone ('functional hypoparathyroidism'). Patients with secondary hyperparathyroidism and hypovitaminosis D had a higher mean corrected calcium, higher 1,25-dihydroxyvitamin D, lower hip bone mineral density and an excess of extracapsular over intracapsular fractures than the 'functional hypoparathyroid' group (P<0.01). CONCLUSION: there is a high prevalence of hypovitaminosis D in active, elderly people living at home who present with a hip fracture. However, secondary hyperparathyroidism occurs in only half of these patients. This subgroup attempts to maintain calcium homeostasis but does so at the expense of increased bone turnover, leading to amplified hip bone loss and an excess of extracapsular over intracapsular fractures. Combination calcium and vitamin D treatment may be effective in preventing a second hip fracture in these patients, but its role in patients with hypovitaminosis D without secondary hyperparathyroidism and 'vitamin D-replete' subjects needs further evaluation.

Secondary prevention of osteoporosis: when should a non-vertebral fracture be a trigger for action?

The burden of non-vertebral fractures is enormous. Hip fractures account for nearly 10% of all fractures (and a much greater proportion in the elderly), while wrist fractures may account for up to 23% of all limb fractures. The best available predictors of non-vertebral fracture risk are low BMD and a tendency to fall. Hip, forearm, proximal humerus and rib fractures have all been associated with low BMD, though ankle fracture is not strongly related to osteoporosis. Although clinical risk factors identify only about one-third of postmenopausal women at increased risk of osteoporotic fracture, the occurrence of one fracture commonly predicts a second fracture. Guidelines are presented for identifying and treating patients at risk of non-vertebral osteoporotic fractures, especially those with a previous fracture, based on the algorithm recently published by the Royal College of Physicians and the Bone and Tooth Society. Prevention of falls and use of external hip protectors may reduce the occurrence of hip fracture. Treatment options for patients presenting with hip fracture include HRT, bisphosphonates, and calcium plus vitamin D, and for Colles' fracture include general measures, HRT, bisphosphonates, or calcitonin plus calcium.

Reproductive, menstrual and menopausal factors: which are associated with bone mineral density in early postmenopausal women?

The associations between a number of reproductive and menopausal factors and bone mineral density (BMD) were studied in a sample of early postmenopausal women. The study included 580 women aged 45-61 years who completed a risk factor questionnaire containing sections on obstetric and menstrual history. BMD measurements were taken at the anteroposterior (AP) spine, greater trochanter, femoral neck, total radius and whole body, along with whole body bone mineral content (BMC). In analyses adjusting for key confounders, number of pregnancies was more strongly associated with increased BMD than number of live births at all sites (p<0.05 at femoral neck and total radius), and menstrual years was more strongly associated with increased BMD than years since menopause (p<0.05 at all sites). Hysterectomized women had a significantly higher adjusted mean BMD than non-hysterectomized women at all sites (AP spine: 0.999 g/cm2 vs 0.941 g/cm2, p<0.001), although there were no significant differences in BMD between hysterectomized women who had a bilateral oophorectomy and those whose ovaries were preserved. Negative associations between the duration of hot flushes and BMD were statistically significant (p<0.05) at the three non-hip sites. In multiple regression analyses containing all reproductive terms, duration of hormone replacement therapy (HRT) use, menstrual years and hysterectomy status were significantly associated with BMD at all five sites, whilst oral contraceptive use before the age of 23 years was significantly associated with increased BMD at all sites except the total radius. Breastfeeding duration, the duration of oral contraceptive use and premenopausal amenorrhea were found to have no association with BMD. Results for whole body BMC were consistent with those for the five BMD sites, across all the variables considered here. These findings confirm the importance of HRT use and duration of menses as predictors of BMD, whilst the results for hysterectomy status and early oral contraceptive use require further consideration.

The use of a whole body index with bone scintigraphy to monitor the response to therapy in Paget's disease.

Bone scintigraphy has long been used to assess Paget's disease and investigate the response to therapy. Objective visual assessment is, however, difficult. The aim of this study was to derive, from a bone scintigram, an index which objectively measured the extent and severity of Paget's disease in the entire skeleton. This whole body index would provide a single numerical value which could be used to monitor the response to therapy in both monostotic and polyostotic disease. Comparison with other methods of assessing the condition, such as biochemical markers and pain scores, would also be possible. The whole body index was developed and used to retrospectively analyse 80 bone scintigrams on 40 patients. The majority of patients (36) received treatment with a bisphosphonate between the two scintigrams. Whole body index was compared with serum alkaline phosphatase measured at the same time; a significant correlation was found (before treatment P=0.001, after treatment P<0.001). The change in whole body index and alkaline phosphatase following treatment with various bisphosphonates was also investigated and a significant correlation found (P<0.001). Whilst performing the analysis it was also noted that the increase in uptake of the radiopharmaceutical was significantly greater in the cortical long bones than in the trabecular axial skeleton. This study suggests that a whole body index may be a suitable tool for assessing the response to treatment in Paget's disease.

Distal forearm fracture history in an older community-dwelling population: the Nottingham Community Osteoporosis (NOCOS) study.

OBJECTIVES: to assess the prevalence of a history of Colles' fracture (occurring after the age of 40 years) and to ascertain the extent of investigation and treatment of osteoporosis in this population. METHODS: we studied subjects aged > or =60 years from the age-sex register of three general practices. We recorded a history of fractures and details of any previous investigation for osteoporosis and treatment with bone-protective drugs. Bone mineral density was performed at the heel using dual-energy x-ray absorptiometry (Lunar PIXI machine). We classified subjects into normal, osteopaenic or osteoporotic according to the machine manufacturer's recommended World Health Organisation 'equivalent T-score thresholds' (0.6 for osteopaenia and 1.6 for osteoporosis). RESULTS: of the 605 subjects invited, we recruited 259 women and 194 men (response rate=74.8%). Twenty-eight (10.8%) of the women and five (2.6%) of the men had a history of Colles' fracture. Of women with a prevalent Colles' fracture, 39% were osteoporotic and 36% were osteopaenic. These rates were significantly greater than in women without a Colles' fracture (19.9% osteoporotic, 29.4% osteopaenic; P=0.018). Assuming the same PIXI thresholds for men, two (40%) of the five men with a history of Colles' fractures were osteoporotic and the rest were osteopaenic, compared with 20.6 and 31.2% of men without a history of Colles' fractures. None of the subjects in the Colles' fracture group had previously been investigated with bone densitometry. Women with and without a history of Colles' fracture did not differ significantly in ever having (32.1% vs 27.2%; P=0.4) or currently having (14.3% vs 10.4%; P=0.4) hormone replacement treatment. None of the men and only one woman with a previous Colles' fracture had ever taken a non-hormone replacement treatment for osteoporosis. CONCLUSIONS: older community-dwelling subjects with previous Colles' fracture have a high prevalence of osteoporosis and are under-investigated and under-treated. Methods for identifying subjects with a previous Colles' fracture need to be developed in primary and secondary care.

The contribution of nutritional factors to osteopenia in the elderly.

Calcium and vitamin D deficiency increase age-related bone loss by causing secondary hyperparathyroidism. Reduced endogenous vitamin D synthesis exacerbates the problem of dietary deficiency and involves elderly people living in their own homes, who are just as much at risk as those living in institutionalized care. The effects of secondary hyperparathyroidism may be offset by hypercalcaemia of the increased bone turnover of immobility, which has a direct adverse effect on the skeleton causing osteoporosis. Active vitamin D analogues are effective in suppressing secondary hyperparathyroidism caused by vitamin D deficiency. However, simple deficiency is optimally treated with parent vitamin D, which has a greater safety margin than active vitamin D therapy (1,25 dihydroxyvitamin D), which requires close monitoring in the elderly.