*Karolina M. Nowak1, Agnieszka Łebek-Szatańska1, Anna Nowakowska-Płaza2, Katarzyna Romanowska-Próchnicka3, 4, Agnieszka Zielińska2, Wojciech Zgliczyński1, Lucyna Papierska1
Prevention and treatment of steroid-induced osteoporosis – recommendations vs clinical practice
Profilaktyka i leczenie osteoporozy posteroidowej – zalecenia vs praktyka kliniczna
1Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warsaw
Head of Department: Professor Wojciech Zgliczyński, MD, PhD
2Department of Rheumatology, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw
Head of Department: Professor Piotr Głuszko, MD, PhD
3Department of General and Experimental Pathology, 2nd Faculty of Medicine, Medical University of Warsaw
Head of Department: Dariusz Szukiewicz, MD, PhD
4Department of Systemic Connective Tissue Diseases, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw
Head of Department: Professor Marzena Olesińska, MD, PhD
Streszczenie
Wstęp. Pacjenci z rozpoznaniem układowej choroby tkanki łącznej przewlekle leczeni glikokortykosteroidami są narażeni na liczne działania niepożądane tego rodzaju terapii. Jednym z najpoważniejszych jest osteoporoza. Nawet u 50% pacjentów z osteoporozą indukowaną steroidami dochodzi do złamań, co w konsekwencji może prowadzić do niepełnosprawności.
Cel pracy. Celem badania było sprawdzenie, czy pacjenci przewlekle przyjmujący glikokortykosteroidy otrzymują profilaktykę i leczenie osteoporozy posteroidowej zgodnie z aktualnymi polskimi wytycznymi. Drugim celem projektu była ocena stopnia niedoboru witaminy D w badanej populacji.
Materiał i metody. Do badania włączono 80 pacjentów z układową chorobą tkanki łącznej, którzy byli leczeni glikokortykosteroidami przez więcej niż 3 miesiące. U wszystkich uczestników badania oznaczono stężenie witaminy D oraz dokonano oceny klinicznej (m.in. historia złamań, densytometria). Analizę statystyczną wykonano przy użyciu programu STATA13.
Wyniki. Stężenia 25(OH)D < 30 ng/ml stwierdzono u 60% wszystkich badanych i u połowy pacjentów leczonych bisfosfonianami. U 46 pacjentów (57,5%) stwierdzono 88 wskazań do farmakoterapii osteoporozy. Odpowiednie leczenie wdrożono jedynie u 16 osób (34,8%) wymagających takiej terapii.
Wnioski. Wyniki badania pokazują, że pacjenci przewlekle leczeni glikokortykosteroidami wymagają ściślejszej kontroli w zakresie prewencji (szczególnie uzupełniania niedoboru witaminy D) oraz leczenia osteoporozy posteroidowej w celu uniknięcia złamań i ewentualnej niepełnosprawności z tego powodu.
Summary
Introduction. Patients with inflammatory connective tissue diseases chronically treated with glucocorticoids are susceptible to many adverse events of this kind of treatment. One of the most serious ones is osteoporosis. Up to 50% of patients with glucocorticoid-induced osteoporosis can suffer from fractures what in consequence can lead to disability.
Aim. The aim of the study was to evaluate if patients chronically treated with glucocorticoids receive an adequate prevention and treatment of glucocorticoid-induced osteoporosis according to current polish recommendations. The second aim was to investigate the vitamin D deficiency status in the studied population.
Material and methods. 80 patients diagnosed with connective tissue diseases treated with glucocorticoids for more than 3 months were enrolled into the study. All participants underwent biochemical (vitamin D serum concentrations) and clinical evaluation (densitometry, medical history of fractures). Statistical analysis was performed with STATA13 software.
Results. 60% of all patients and 50% of patients treated with bisphosphonates had vitamin D serum levels below recommended values (< 30 ng/ml). 46 patients (57.5%) had 88 indications for treatment. Only 16 (34.8%) participants who required treatment received pharmaceutical therapy.
Conclusions. The results of the study clearly show that patients chronically treated with glucocorticoids require more strict controls in terms of osteoporosis prevention (especially vitamin D supplementation) and treatment in order to prevent fractures and disability.
INTRODUCTION
Systemic glucocorticoids (GCS) have unquestionable place in treatment of autoimmune and inflammatory disorders. Unfortunately despite their positive effects, GCS can cause serious adverse events such as osteopenia and glucocorticoid-induced osteoporosis (GIO) (1). The use of GCS is the most common cause of iatrogenic and secondary osteoporosis, as well as the early-onset osteoporosis (before 50 years of age) (2). The mechanisms of GCS impact on bone loss are as follows (3, 4):
– increase of calcium excretion and decrease in gastrointestinal calcium resorption which lead to increase of PTH concentration,
– decrease of production of osteoblast precursors, osteoblast proliferation and activity (plus premature apoptosis),
– loss of function and increased apoptosis of osteocytes (5),
– prolonged osteoclast lifespan (4),
– suppressive effect on TGF-β, insulin-like growth factor-1 (IGF-1) and growth hormone (GH),
– increased bone resorption (in some cases) caused by hypogonadism and secondary hyperparathyroidism,
– reduction in collagen type 1 synthesis,
– decrease of muscle mass (which cause also increased risk of falls).
Additionally, the underlying rheumatic inflammatory disease can contribute in bone remodeling leading to decrease in formation and increase in resorption (2). In rheumatoid arthritis there is a two-fold increase in risk of hip and vertebral fractures, even regardless of the GCS use (6). The increased risk of bone loss is observed immediately after GCS admission and is the highest in first 3-6 months of treatment (7), afterwards the decline of bone mineral density is slower. There is also an increased risk of fractures, especially vertebral fractures (or ribs) as the use of GCS affects more trabecular bone than cortical bone (i.e. femur) (8). Of note, due to low bone quality in patients treated with GCS, fractures occur more often than it results from a decrease in bone mineral density (BMD), more often within the same BMD as in postmenopausal osteoporosis and even in high BMD values (9). The negative effect of GCS is potentially reversible after cessation of therapy which also includes the decrease in fracture risk (10). High cumulative and daily dose of GCS increase risk of fracture (5). However, data suggest that there is no “safe dose” of GCS in terms of osteoporosis prevention (5). Thus, all patients treated chronically should be properly managed (8, 11-13). The main goal is to prevent fractures and if they occur – to reduce the risk of further fractures.
AIM
The aim of the study was to investigate if and to what extent patients chronically treated with GCS receive optimal prevention and treatment of osteoporosis according to current polish recommendations (11-13). The second objective was to evaluate the vitamin D deficiency status in patients with inflammatory connective tissue diseases treated chronically with GCS.
MATERIAL AND METHODS
Eighty patients, treated with glucocorticoids for at least three months, referred to the Department of Endocrinology of Centre of Postgraduate Medical Education in Warsaw underwent clinical evaluation including: medical history of the daily, cumulative dose and type of GCS, daily dose of calcium and vitamin D intake, history of fractures, family history of osteoporosis. All patients were evaluated for serum vitamin D and calcium levels. BMD was assessed by dual-energy X-ray absorptiometry (g/cm2) at the femoral neck and lumbar spine (L1-L4) using the General Electric Healthcare Lunar Prodigy Advance densitometer.
The exclusion criteria were as follows: pregnancy, corticoid treatment for less than three months, diagnosed hypercortisolemia before corticoid treatment, cancer, liver or renal failure.
The study was approved by the Bioethics Committee and all patients gave their written consent to participate in the study.
Patients were divided into two groups: group 1 < 40 years of age and group 2 ≥ 40 years of age. The 10-year risk of major osteoporotic fracture was calculated for group 2 using the polish version of FRAX tool: https://www.sheffield.ac.uk/FRAX/tool.jsp.
Statistical analysis was performed with STATA13 software. The measured continuous parameters were described by the minimum and maximum value, mean and standard deviation (SD). Compatibility with a normal distribution was checked with test of Shapiro-Wilk and equality of variance with Bartlett’s test. Next, the obtained mean of the two groups was compared using Student’s t test for two variables. In the absence of normal distribution of one of the variables, the nonparametric U-Mann-Whitney-Wilcoxon test was used. When inequality of variances of normally distributed variables was found the Welch test was performed.
Definitions of vitamin D serum concentrations (14): sufficient level ≥ 30 ng/ml, insufficiency 20-30 ng/ml, deficiency < 20 ng/ml and overt hypovitaminosis < 10 ng/ml (15). Definitions of reduced bone mineral density based on densitometry (11):
– > -1 SD: normal value,
– ≤ -1 SD to > -2.5 SD: osteopenia,
– ≤ -2.5 SD: osteoporosis,
– ≤ -2.5 SD and fracture: advanced osteoporosis.
Indications for treatment in patients chronically treated with GCS according to current polish recommendations (11-13):
1. Any low-energy fracture (treatment should be started even without performing densitometry).
2. High risk of fracture (≥ 10%) assessed using FRAX calculator.
3. Moderate risk of fracture (5-10%) assessed using FRAX calculator.
4. BMD T-score (in femur neck) ≤ -1.5 SD (in patients older than 50 years) and Z-score ≤ -1.5 in younger patients (for relevant age and sex).
5. BMD T-score (in lumbar spine L1-L4) ≤ -2.5 SD – irrespective of age.
6. Patients (> 65 years of age) at the beginning of GCS therapy when they are scheduled to receive ≥ 7.5 mg of prednisone (or equivalent) for more than 3 months (obligatory preventive osteoporosis treatment) (12, 13).
7. Postmenopausal women with accelerated bone metabolism (elevated concentration of bone turnover markers, CTX, collagen type 1 crosslinked C-telopeptide or P1NP, procollagen 1 aminoterminal propeptide) which increase their fracture risk (i.e. assessed by FRAX tool) from low to moderate or from moderate to high.
In 2017 the new recommendation was given: in patients ≥ 50 years of age treated with > 5 mg of prednisone/day (or equivalent) for more than 3 months with additional risk factors of fracture, preventive bisphosphonate treatment should be considered (12, 13).
RESULTS
The study included 80 patients during chronic glucocorticoid therapy. Seventeen patients suffered from systemic lupus erythematosus (SLE), 35 were diagnosed with rheumatoid arthritis, 8 with polymyalgia rheumatica, 6 with polymyositis, 5 with mixed connective tissue disease, 3 with unclassified arthritis, 1 with Wegener granulomatosis and 3 with Sjogren’s syndrome. The basic characteristic of patients were presented in table 1.
Tab. 1. Basic characteristic of patients
Characteristic of patients
Total | Group 1
66 | Group 2
14 |
Age (yr)
mean ± SD | 40-77
58.6 ± 9.6 | 20-38
30.2 ± 5.5 |
Women
Men | 54
12 | 10
4 |
Time of steroid treatment (in months)
mean ± SD | 5.9-363.7
98.2 ± 94.9 | 2.75-174.4
54 ± 52.2 |
Daily dose (in miligrams)
(equivalent of prednisone)
mean ± SD | 1.25-37.5
6.9 ± 6.5 | 2.5-50
14.55 ± 14.8 |
Cumulative dose (in grams)
(equivalent of prednisone)
mean ± SD | 0.345-135.05
25.32 ± 30.9 | 1.66-101.86
21.06 ± 24.94 |
BMI (kg/m2)
mean ± SD | 14.7-46.34
26.4 ± 25.6 | 16.4-42.4
24.7 ± 6.8 |
25(OH)D level (ng/ml)
mean ± SD | 7.66-76.6
32.14 ± 12.5 | 7.6-33.92
21.78 ± 7.46 |
Vitamin D dose (IU) (N = 56)
mean ± SD | 200-6000
2047 ± 1096 | 400-2000
1430 ± 676.6 |
Results for group 1 (≥ 40 years of age, 66 patients)
55 patients (out of 66) were ≥ 50 years of age. Two patients had osteopenia (treated with zoledronate and ibandronate) and 1 had advanced osteoporosis with fracture treated with denosumab before GC treatment.
Bone mineral density assessment
T-score for femoral neck:
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Piśmiennictwo
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