Biomarks in secondary osteoporosis

The existence of a metabolic disease in rheumatoid arthritis in distant zones of the active synovitis areas, remains controversial. Indeed, the variations found, by different authors, in PTH, in alkaline phosphatase and in serum and/or in the calcium urinary values, as well as in phosphate and hydroxyproline, have not clarified this problem, despite the demonstration by histomorphometry and by densitometrical methods, of a greater loss of the bone mass in rheumatoid arthritis. At the same time, metabolic changes in sexual hormones, primary or secondary, can modulate the immune response and interfere in the clinic expression of rheumatoid arthritis and also in the bone turnover. Therefore, the purpose of this study was to compare some parameters of the bone metabolism and of the hormonal condition, in women with rheumatoid arthritis, with and without corticotherapy and in an age related control group. In Group RA (patients), we found relatively higher levels of phosphates, alkaline phosphatase and osteocalcine, just as in the nephrogenic c'AMP and the hydroxyproline/creatinine quotient. The blood levels of calcitonin, PTH, T3, T4, cortisol and estradiol did not show significant differences between the 2 groups, although they were lower in Group RA. On the contrary, the plasma levels of testosterone, of 4-androstenodione and DHEA.S were significantly reduced in patients with rheumatoid arthritis. These results are compatible with the existence of bone metabolic hyperactivity in rheumatoid arthritis, which can be related, directly or indirectly to the reduced androgens plasma levels, since these seem to play a protective role in auto-immune diseases and also on the bone metabolism. The presence of lower calcitonin levels in R.A. (although statistically not significant) will, eventually, reinforce even more this increased bone turnover.     

The management of secondary osteoporosis

Secondary osteoporosis is common among patients being evaluated for osteoporosis. All men and premenopausal women with unexplained bone loss or a history of a fragility fracture should undergo a work-up for secondary osteoporosis. Also, postmenopausal women with risk factors for secondary osteoporosis should be carefully evaluated. The evaluation should include a thorough history, physical examination, bone mineral density testing, and laboratory testing. While there is no consensus for a cost-effective laboratory evaluation, some recommendations include: 25-hydroxyvitamin D, parathyroid hormone (PTH), serum and urine calcium, phosphate, creatinine, liver function tests, a complete blood count, testosterone in men, and thyroid-stimulating hormone. After a thorough review of the evaluation for secondary osteoporosis, this chapter reviews the pathophysiology and treatment of secondary osteoporotic disorders, including vitamin D insufficiency, osteomalacia, the osteoporosis of erosive inflammatory arthritis, ankylosing spondylitis, systemic lupus erythematosus, and osteoporosis related to anti-androgenic therapy for prostate cancer and aromatase inhibitor therapy for breast cancer. Physicians have a significant responsibility to evaluate and treat the underlying medical problem that is the cause of secondary osteoporosis and to optimize bone health in the individual patient.     

Bisphosphonate therapy in children with secondary osteoporosis

BACKGROUND: Increased bone fragility requiring effective treatments is a complication of various chronic conditions in children. Bisphosphonates, highly effective in the treatment of adults with osteoporosis, have also been used in children with secondary osteoporosis. However, results obtained in adults cannot be readily extrapolated to children due to differences in the pathophysiology and progression of the disease as well as in the pharmacokinetics of bisphosphonates. CONCLUSIONS: Available results of studies of bisphosphonates in children with secondary osteoporosis do not yet support their recommendation as standard therapy. Their use should be restricted to patients with fragility fractures and low bone mass.     

Bisphosphonate therapy for secondary osteoporosis: adult perspective

BACKGROUND: A number of disease states and drugs can upset the balance between bone formation and resorption resulting in increased fracture risk. Glucocorticoids are the most recognized cause of secondary osteoporosis. Hypogonadism, weight loss, and chronic inflammation are other contributors to bone loss in a variety of disease states. Bisphosphonates are potent inhibitors of bone resorption, and there is a variety of secondary osteoporosis where they produce substantial increases in bone density and reduce fracture risk by about 50%. Upper gastrointestinal tract intolerance with oral agents and a flu-like syndrome with intravenous bisphosphonates are the principal adverse effects associated with their use. CONCLUSIONS: Numerous disease states and medications can adversely affect the skeleton. Additional effects of aging and menopause can substantially increase an individual's fracture risk. It is important that physicians assess fracture risk in susceptible patients and initiate treatment when indicated.     

Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis

Background

The mechanism of osteoporosis with fracture secondary to mastocytosis is little known, and its treatment is poorly codified.

Methods

Ten patients with a mean age of 52.5 years with systemic mastocytosis and osteoporotic fractures were treated with interferon alpha 1.5 million U 3 times per week, combined with monthly pamidronate infusions (1 mg/kg) for 2 years, followed by pamidronate infusions every 3 months.

Results

Before treatment, the mean number of vertebral fractures was 3.5, spinal T-score was −3 ± 1, hip T-score was −1.9 ± 0.7, serum C-terminal telopeptide was 357 ± 258 pg/mL (N = 80-800), bone alkaline phosphatase was 20 ± 3.2 IU (N = 8-25), and tryptase was 49 ± 36 μg/mL (N < 10). Interferon alpha was discontinued in 2 patients because of poor tolerance. Mean follow-up was 60 months. No patient developed a fracture under treatment. In the 8 patients treated with interferon alpha and pamidronate, the mean annual increase in spinal bone mineral density was 12.6% ± 5.6% and 1.93% in hip bone mineral density. Serum C-terminal telopeptide decreased by 66%, bone alkaline phosphatase decreased by 25%, and tryptase decreased by 34%. In the 2 patients treated with pamidronate alone, mean annual bone mineral density increase was 2.4% ± 0.1% at the spine and 0% ± 01% at the hip.

Conclusion

Osteoporosis secondary to mastocytosis mainly affects trabecular bone, and markers of bone remodeling are normal. Combined treatment with low doses of interferon and pamidronate markedly increased bone density.     

国内继发性骨质疏松动物模型研究概论

社会老龄化进度的加快,骨质疏松症日益受到重视。随着治疗和预防骨质疏松症药物的毒副作用的研究、新药开发应用以及机理方面的研究不断深入,对骨质疏松症的动物模型提出了更高的要求。现就对国内继发性骨质疏松动物模型的复制方法和模型形成机制做一概述。     

Postmenopausal osteoporosis as a manifestation of renal hypercalciuria with secondary hyperparathyroidism

An apparently unique presentation of osteoporosis was encountered in eight postmenopausal women (mean age, 56.8 yr). They had renal hypercalciuria, since they had fasting hypercalciuria [0.17 +/- 0.04 (+/- SD) mg/100 ml glomerular filtrate (GF)] in the setting of normocalcemia and parathyroid stimulation (high serum immunoreactive PTH and/or urinary cAMP). Serum 1,25-dihydroxyvitamin D was not significantly different (28 +/- 7 vs. 34 +/- 2 pg/ml) from that in a nonelderly control group, but fractional intestinal calcium (Ca) absorption was significantly lower (0.382 +/- 0.123 vs. 0.49 +/- 0.06; P less than 0.025). Thus, the patients did not have compensatory intestinal hyperabsorption of Ca despite PTH excess. Treatment with hydrochlorothiazide (50 mg/day) produced a decline in fasting urinary Ca (to 0.07 +/- 0.02 mg/100 ml GF; P less than 0.01), serum PTH (from 39 +/- 19 to 21 +/- 1 microliters eq/ml; P less than 0.05), and urinary cAMP excretion (from 5.30 +/- 0.57 to 3.57 +/- 0.59 nmol/100 ml GF; P less than 0.0025). The results suggested that hyperparathyroidism was secondary. Histomorphometric analysis of bone showed reduced trabecular bone volume without mineralization defect, compatible with osteoporosis. Four of eight patients had high or high normal fractional resorption surfaces, fractional formation surfaces, and fractional osteoid volumes. That these abnormalities may reflect PTH-dependent osteoclastic resorption and bone turnover was supported by the reduction of these indices after correction of secondary hyperparathyroidism with hydrochlorothiazide therapy. The remaining four patients, however, had normal histomorphometric results. In summary, postmenopausal osteoporosis may occur sometimes with renal hypercalciuria and secondary hyperparathyroidism. The lack of compensatory intestinal hyperabsorption of Ca predisposes to negative Ca balance, and the hyperparathyroid state may be manifested by stimulated osteoclastic and osteoblastic activities.     

Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women

Our purpose in this study was to determine the prevalence of undetected disorders of bone and mineral metabolism in women with osteoporosis and to identify the most useful and cost-efficient screening tests to detect these disorders. A cross-sectional study was conducted among 664 postmenopausal women with osteoporosis at the Osteoporosis and Metabolic Bone Disease Program at the Mount Sinai Hospital in New York between January 1992 and June 1996. Women without a history of diseases or medications known to adversely affect bone who completed extensive laboratory testing including complete blood count, chemistry profile, 24-h urinary calcium, 25(OH)vitamin D, and PTH were included. Among 173 women who met the inclusion criteria for the study, previously undiagnosed disorders of bone and mineral metabolism were identified in 55 women (32%). Disorders of calcium metabolism and hyperparathyroidism were the most frequent diagnoses. A testing strategy involving measurement of 24-h urine calcium, serum calcium, and serum PTH for all women and serum TSH among women on thyroid replacement therapy would have been sufficient to diagnose 47 of these 55 women (85%) at an estimated cost of $75 per patient screened. Previously undiagnosed disorders affecting the skeleton are common in otherwise healthy women with low bone density. A simple testing strategy is likely to identify most such disorders.     

Recommendations based on the evidence for secondary prevention of fractures/osteoporosis

For Japanese women aged 65 years and older and men aged 75 years and older, osteoporosis screening through the use of DXA is recommended. For those with risk factors of osteoporosis and bone fracture among postmenopausal women younger than 65 years of age and men younger than 75, osteoporosis screening is considered to be beneficial. Regarding effectiveness of the screening among perimenopausal women, there is simply no evidence to recommend the screening. Further investigation is necessary into the effectiveness of using QUS for osteoporosis screening, as accuracy tends to suffer depending on the type of QUS device used and the level of values measured.     

Primary and secondary osteoporosis. The important role of internal medicine in its differential diagnosis

Bone metabolism as an important part of internal medicine is covered by endocrinologists, rheumatologists and nephrologists. Primary osteoporosis is an inheritable metabolic bone disease, which can be strongly modified by lifestyle, ageing and underlying diseases. Chronic inflammatory diseases, disorders of metabolism and nutritional deficits enhance the risk. Secondary osteoporosis is caused by endocrinological disorders and drugs such as glucocorticoids. It is the task of internists to clinically recognise and diagnose prominent individual risk factors for primary osteoporosis and underlying diseases for secondary osteoporosis. The key competence of internal medicine in metabolism, hormone-related disorders, malignant diseases and in handling complex medical treatment modalities represents an indispensable segment of an interdisciplinary network approach in patient care, research and teaching. This network includes orthopaedic surgery, paediatrics and gynaecology in addition to other specialties.     

Vertebral fractures and bone mineral density in idiopathic, secondary and corticosteroid associated osteoporosis in men

OBJECTIVE: To investigate bone mineral density (BMD) in men with symptomatic osteoporosis and compare BMD in patients with idiopathic, secondary and corticosteroid associated osteoporosis. METHODS: Age, number of vertebral fractures at presentation and BMD were investigated in men presenting to a bone metabolism clinic with idiopathic (n=105; group 1), secondary (n=67; group 2) and corticosteroid osteoporosis (n=48; group 3). BMD was measured in 176 healthy men (controls). Osteoporosis was diagnosed if there was >/=20% vertebral deformity. RESULTS: Age at peak BMD in controls was 20-29 years at spine (LS-BMD) and femoral neck (FN-BMD). LS-BMD did not change with age but FN-BMD decreased in controls and groups 1 and 2. Mean (SD) age was similar in groups 1 (62.8 (11.5) years, 2 (60.2 (11.0)) years and 3 (62.7 (10.4) years with 45%, 51% and 40% of patients respectively presenting before 60 years. Back pain, present for up to 12 months, was the commonest cause of referral. Vertebral fractures at presentation averaged mean (SD) 2.51 (1.9) in group 1, 2.76 (2.2) in group 2 and 2.48 (1.8) in group 3. LS-BMD Z scores and T scores were more negative in group 1 patients with /= 1 fracture.     

Suppressed TSH levels secondary to thyroxine replacement therapy are not associated with osteoporosis

OBJECTIVE Recent studies have suggested that patients receiving thyroxine are at increased risk of osteoporosis. We set out to measure bone mineral densities in two groups of post-menopausal women receiving thyroxine replacement therapy (those with serum TSH levels persistently suppressed or non-suppressed) and to compare the results in both groups with those of the local control population. DESIGN Cross-sectional study. PATIENTS Seventy-eight post-menopausal women who had been treated with thyroxine for primary autoimmune or idiopathic hypothyroidism for a minimum of 5 years, 44 with TSH persistently suppressed and 34 non-suppressed. One hundred and two control subjects. MEASUREMENTS Forearm bone mineral density at proximal and distal sites as measured by single-photon absorptiometry. RESULTS Results were expressed as Z-scores, i.e. number of standard deviations from the mean of a 5-year age-band from the local control population. Mean Z-scores at proximal and distal sites for the non-suppressed patients were -003 and -007 and for the suppressed patients were 0 20 and -0 25, representing a decrease in bone mineral density of at most 5% in the suppressed patients. The differences between the three groups were not statistically significant. CONCLUSION In this patient population, the reduction in bone mineral density due to thyroxine is small. It is unlikely to be of clinical significance and should not on its own be an indication for reduction of thyroxine dose in patients who are clinically euthyroid.     

Application of biochemical markers of bone metabolism in the assessment of secondary osteoporosis in rheumatoid arthritis patients

Assessment of abnormality of bone mineral metabolism in osteoporosis is made easier by means of newly developed bone metabolic markers. In primary osteoporosis, patients who show high turnover of bone metabolism have high risk of fracture. In RA patients, as bone metabolism is usually high turnover and incidence of insufficiency stress fracture is very frequent, assessment of bone metabolism is more important. Because of poor activity of daily living of RA patients, development of convenient method to collect specimen for examination of bone metabolism and to measure local bone metabolism are important.     

The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis

Three patients with osteoporosis secondary to systemic mastocytosis are described. With the exception of the typical rash of urticaria pigmentosa, spinal pain caused by osteoporosis was the most prominent symptom. Intermittent single i.v. infusions of pamidronate have controlled pain an improved lumbar spine bone density.      

Comparison of the efficacy of denosumab and bisphosphonates for treating secondary osteoporosis in patients with rheumatoid arthritis

Objectives: This study aimed to investigate the efficacy of denosumab (compared with that of bisphosphonates) for preventing secondary osteoporosis and inflammation caused by excessive bone resorption in Japanese rheumatoid arthritis (RA) patients never previously treated for osteoporosis.

Methods: Ninety-eight patients with coexisting RA and osteoporosis were enrolled. The patients were subdivided by whether they were treated with denosumab (n?=?49) or traditional bisphosphonates (n?=?49). RA disease activity, bone turnover markers, and bone mineral density (BMD) were compared between the two groups before treatment, and after 6 and 12 months of treatment.

Results: There was no significant difference between the groups in any of the disease activity indices and BMD at any of the measured time points. With regard to bone metabolism, denosumab significantly reduced bone-specific alkaline phosphatase at 6 and 12 months compared with pretreatment, but had no effect on tartrate-resistant acid phosphatase 5b levels, suggesting an effect on the bone formation rate, but not on the bone resorption rate.

Conclusions: Neither denosumab nor bisphosphonates could suppress inflammation or RA disease activity, but denosumab significantly suppressed a marker of bone metabolism in Japanese RA patients never previously treated for osteoporosis.     

Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study

Osteoporosis is prevalent in men with an estimated one in eight men older than 50 years suffering from osteoporotic fracture, and a higher mortality rate after fracture among men compared with women. There are few approved therapies for osteoporosis in men. This observational study assesses the efficacy and safety of risedronate in the treatment of men with primary and secondary osteoporosis. A single-center, open label, randomized, prospective 1-year study was conducted in men with primary or secondary osteoporosis. Patients were randomized to risedronate (risedronate 5 mg/day plus calcium 1,000 mg/day and vitamin D 800 IU/day) or control groups (alfacalcidol 1 μg/day plus calcium 500 mg/day or vitamin D 1,000 IU/day plus calcium 800 mg/day). Bone mineral density (BMD) measurements, X-rays of the spine, a medical history and physical exam, and patient self-assessments of back pain were performed at baseline and 12 months. Blinded semi-quantitative fracture assessment was conducted by a radiologist. A total of 316 men with osteoporosis were enrolled in the trial (risedronate, n=158; control, n=158). At 1 year lumbar spine BMD increased by 4.7% in the risedronate group versus an increase of 1.0% in the control group (P<0.001). Significant increases in BMD at the total hip and femoral neck were also observed with risedronate compared with the control group. The incidence of new vertebral fracture in the risedronate group was reduced by 60% versus the control group (P=0.028). Daily treatment with risedronate for 12 months significantly increased BMD at the lumbar spine, femoral neck and total hip and significantly reduced the incidence of new vertebral fractures. This is the first prospective, randomized, controlled trial to demonstrate a significant reduction in vertebral fractures in 1 year in men with primary or secondary osteoporosis.