Severity and pattern of bone mineral loss in endocrine causes of osteoporosis as compared to age-related bone mineral lossD Dutta1, P Dharmshaktu1, A Aggarwal1, K Gaurav1, R Bansal1, N Devru1, UC Garga2, B Kulshreshtha1
1 Department of Endocrinology, Post-graduate Institute of Medical Education and Research (PGIMER) and Dr. Ram Manohar Lohia (RML) Hospital, New Delhi, India
2 Department of Radiology, Post-graduate Institute of Medical Education and Research (PGIMER) and Dr. Ram Manohar Lohia (RML) Hospital, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.183170
Source of Support: None, Conflict of Interest: None
Background: Data are scant on bone health in endocrinopathies from India. This study evaluated bone mineral density (BMD) loss in endocrinopathies [Graves' disease (GD), type 1 diabetes mellitus (T1DM), hypogonadotrophic hypogonadism (HypoH), hypergonadotropic hypogonadism (HyperH), hypopituitarism, primary hyperparathyroidism (PHPT)] as compared to age-related BMD loss [postmenopausal osteoporosis (PMO), andropause]. Materials and Methods: Retrospective audit of records of patients >30 years age attending a bone clinic from August 2014 to January 2016 was done. Results: Five-hundred and seven records were screened, out of which 420 (females:male = 294:126) were analyzed. A significantly higher occurrence of vitamin D deficiency and insufficiency was noted in T1DM (89.09%), HyperH (85%), and HypoH (79.59%) compared to age-related BMD loss (60.02%; P < 0.001). The occurrence of osteoporosis among females and males was 55.41% and 53.97%, respectively, and of osteopenia among females and males was 28.91% and 32.54%, respectively. In females, osteoporosis was significantly higher in T1DM (92%), HyperH (85%), and HypoH (59.26%) compared to PMO (49.34%; P < 0.001). Z score at LS, TF, NOF, and greater trochanter (GT) was consistently lowest in T1DM women. Among men, osteoporosis was significantly higher in T1DM (76.67%) and HypoH (54.55%) compared to andropause (45.45%; P = 0.001). Z score at LS, TF, NOF, GT, and TR was consistently lowest in T1DM men. In GD, the burden of osteoporosis was similar to PMO and andropause. BMD difference among the study groups was not significantly different after adjusting for body mass index (BMI) and vitamin D. Conclusion: Low bone mass is extremely common in endocrinopathies, warranting routine screening and intervention. Concomitant vitamin D deficiency compounds the problem. Calcium and vitamin D supplementations may improve bone health in this setting.
Keywords: Bone mineral density (BMD), Graves′ disease (GD), hypogonadism, hypopituitarism, osteoporosis
A large number of endocrinopathies are known to be associated with impaired bone health. Studies have demonstrated osteopenia and increased fracture risk in type 1 diabetes mellitus (T1DM). ,,, Studies involving young adults with Graves' disease (GD) have demonstrated significantly lower bone mineral density (BMD) at the spine, hip, and wrists. , Hypogonadism in both the sexes have been linked to low BMD and bone health. , Both the prototypes of primary hypogonadism in females and males (Turner's syndrome and Klinefelter's syndrome, respectively) are associated with lower BMD and quality, resulting in increased fracture risk. , Childhood- and young adulthood-associated growth hormone deficiency (GHD) have been associated with reduced BMD and content. ,, Secondary hypogonadism, either isolated or as a part of panhypopituitarism (secondary hypogonadism, growth hormone deficiency, along with other pituitary hormone deficiencies) is a well-known cause of secondary osteoporosis. 
In spite of these considerable data available globally, similar data are scant from Indian patients. There is in general a lack of awareness, and bone health assessment is neglected in endocrine causes of bone mineral loss in India. Till date, no study has attempted to quantify the burden of osteoporosis and osteopenia in endocrine causes of osteoporosis in India. This study aimed to audit the current status of severity and pattern of bone mineral loss in patients with endocrine causes of bone mineral loss (GD, T1DM, hypogonadotrophic and hypergonadotropic hypogonadism, hypopituitarism, primary hyperparathyroidism) attending the endocrinology services of a tertiary care center in northern India. This study also aimed to compare the severity of bone mineral loss in different endocrinopathies with the more commonly recognizable forms of bone mineral loss, for which there is increased awareness and screening is commonly done, viz., postmenopausal osteoporosis (PMO) and andropause (age-related bone mineral loss in males).
The department of endocrinology has been running a dedicated bone and metabolism clinic since August 2014 with an intention of early detection of bone mineral loss, along with the institution of appropriate therapeutic intervention in patients with different etiologies of osteoporosis. Apart from screening for age-related bone mineral loss [evaluation of BMD in postmenopausal women and men >70 years of age with/without clinical and/or biochemical evidence of hypogonadism (andropause)], a conscious effort is made to screen the bone mineral health in patients with various endocrinopathies, which have been linked to impaired bone health (GD, T1DM, hypogonadism, and primary hyperparathyroidism, among others). Detailed clinical records are maintained of all the patients attending the bone and metabolism clinic.
This is a retrospective cross-sectional study of the records of patients who attended the bone and metabolism clinic of the hospital from August 2014 to January 2016. Only the records of patients >30 years of age were considered. This is because peak bone mass is usually reached by 22 years and 29 years of age in men and women, respectively, at the lumbar spine and earlier at other sites.  Comparison of BMD would be more meaningful once peak bone mass has been achieved. Records with incomplete data were excluded. Data on anthropometry, calcium metabolism (serum calcium, phosphate, vitamin D, parathyroid hormone), and BMD were collected. The study protocol and flow of patients have been elaborated in [Figure 1]. The institutional ethics committee had approved the study protocol.
All patients had undergone BMD assessment at our institute by dual-energy x-ray absorptiometry (Discovery Wi Series, serial number: 84571; Hologic Inc., Waltham, MA, USA) at the lumbar spine (L1-L4 anteroposterior), left proximal femur (neck, greater trochanter, and Ward's triangle), and left forearm regions (radius 33% and radius total). Quality control procedures were done as per the manufacturer's recommendations. A trained technician in the department performed all the scans. The instrument was calibrated on a daily basis using the phantom provided by the manufacturer and the coefficient of variation (CV) at different sites was found to be <1.0% over the duration of the study. The BMD of the subjects was recorded in terms of absolute mineral content (in g/cm 2 ) at various sites. Due to a significant difference in age of the patients in different groups, Z score [number of standard deviations (SDs) away from the average value of age- and gender-specific reference group] was used to compare BMD across groups. Osteoporosis at any site was diagnosed if Z score at any site was <-2 SD.  Osteopenia at any site was diagnosed if Z score was between -1SD and -2 SD.  Z score at Ward's triangle was not used for diagnosis of osteoporosis or osteopenia.
Chemiluminescent microparticle immunoassay (VITROS® ECiQ Immunodiagnostic System, Johnson and Johnson, USA) was used for estimation of 25-hydroxy-vitamin-D and intact parathyroid hormone (iPTH) at our institute. Serum 25-hydroxy-vitamin-D (25OHD) assay had analytical sensitivity of 8.0 ng/mL, analytical range of 8-150 ng/mL, and intra- and inter-assay coefficient of variation (CV) of 3.4% and 5.5%, respectively. iPTH assay had analytical sensitivity of 3.4pg/mL, analytical range of 3.4-5,000 pg/mL, and intra-assay and inter-assay CV of 2.1% and 4.7%, respectively. Serum calcium, phosphate, alkaline phosphate, and renal function tests were done using clinical chemistry autoanalyzer based on dry chemistry microslide technology (VITROS® 350 chemistry system, Johnson and Johnson, Raritan, NJ, USA).
Normality of the distribution of variables was checked using the Kolmogrov-Smirnov test. Continuous variables were expressed as mean ± SD. Nonnormally distributed (skewed) variables were expressed as median (range). Analysis of variance (ANOVA) with post hoc analysis and Kruskal-Wallis nonparametric (ANOVA) with Dunn's postcorrection was performed for normally and nonnormally distributed variables, respectively. Analysis of covariance (ANCOVA) was done to adjust for the impact of body mass index (BMI) and vitamin D levels on BMD difference at different sites, among the different study groups. Chi-squared tests were used for categorical variables. P < 0.05 was considered to be statistically significant. Statistical Package for the Social Sciences (SPSS) version 16 (Chicago, IL, USA) was used for analyses.
A total of 507 patient records were screened, out of which 433 records that fulfilled all the criteria were evaluated [Figure 1]. Thirteen records with a small number of patients in diagnosis groups were excluded for analysis [hypoparathyroidism (n = 7), Klinefelter's syndrome (n = 2), celiac disease (n = 2), myeloma (n = 1), and bone metastasis (n = 1)]. A total of 420 records [females (n = 294) and males (n = 126)] were finally analyzed. Vitamin D deficiency (25OHD <20 ng/mL) and insufficiency (20-30 ng/mL) were significantly more common in patients with T1DM [89.09% (49/55)], hypergonadotropic hypogonadism [85% (17/20)], and hypogonadotrophic hypogonadism [79.59% (39/49)] as compared to those with age-related bone mineral loss (PMO and andropause) [60.02% (118/196)] (P < 0.001). The occurrence of vitamin D deficiency and insufficiency in GD and primary hyperparathyroidism (PHPT) was 67.12% (49/73) and 66.67% (18/27), respectively [Table 1] and [Table 2]. The occurrence of osteoporosis among females and males in our cohort was 55.41% (164/296) and 53.97% (68/126), respectively. The occurrence of osteopenia among females and males in our cohort was 28.91% (85/294) and 32.54% (41/126), respectively.
Among females, age was significantly different among the etiology groups with the highest being in women with PMO and lowest in hypergonadotropic hypogonadism followed by T1DM and hypogonadotrophic hypogonadism [Table 1]. The occurrence of osteoporosis and osteopenia was significantly higher in females with T1DM, hypergonadotropic hypogonadism, and hypogonadotrophic hypogonadism as compared to PMO [Table 1]. Absolute areal BMD at the lumbar spine (P = 0.001), total femur (P = 0.016), and neck of femur (P = 0.033) was significantly different among the groups, with the lowest being in patients with T1DM [Table 1]. Z score, which adjusts for the age of the individual, was significantly different among the groups of patients at all the different sites at the hip, wrist, and spine [Table 1]. Z score at the lumbar spine, total femur, neck of femur, and greater trochanter was lowest in patients with T1DM. Total radius Z score was the lowest in patients with PHPT. BMI, which has a positive impact on BMD, was significantly different, with the lowest being in females with T1DM [Table 1]. Serum vitamin D was also significantly different across the groups, being the highest in women with PMO and lowest in women with hypogonadism [Table 1]. After adjusting for BMI and vitamin D levels, the significant differences in the absolute areal BMD at the lumbar spine, total femur, and neck of femur were lost [lumbar spine (P = 0.129), total femur (P = 0.195), and neck of femur (P = 0.099)].
In men too, the age was significantly different among the groups with the lowest in men with T1DM, and highest in those diagnosed with andropause [Table 2]. Occurrence of osteoporosis was significantly different among men with different underlying etiologies, with the highest being in T1DM followed by hypogonadotrophic hypogonadism [Table 2]. In men, absolute areal BMD was significantly different across groups at the lumbar spine (P = 0.002) and greater trochanter (P < 0.001), with the lowest being in men with T1DM [Table 2]. Z score, which adjusts for the age of the individual, was significantly different among the groups at the lumbar spine, total femur, neck of femur, greater trochanter, Ward's triangle, and radius total, being consistently lowest in men with T1DM [Table 2]. BMI was significantly different among the groups, with the lowest being in men with T1DM and highest in men with hypogonadotrophic hypogonadism and andropause [Table 2]. Serum vitamin D was also significantly different among the groups, with the lowest being in men with T1DM and highest in men with andropause [Table 2]. After adjusting for BMI and vitamin D levels, the significant differences in the absolute areal BMD at the lumbar spine and greater trochanter were lost [lumbar spine (P = 0.152), greater trochanter (P = 0.841)].
Further detailed analysis of occurrence of osteoporosis at different individual sites of BMD assessment revealed that it was significantly different among the different etiology groups in both the sexes, with the highest occurrence rates consistently being in patients with T1DM [Table 3]. Detailed analysis of occurrence of osteopenia at different individual sites of BMD assessment revealed that it was significantly different only at the lumbar spine and wrist in males where the highest occurrence was noted in men with T1DM and andropause [Table 4].
More than half the patients in our cohort had osteoporosis (55.24%) and another 30% had osteopenia. This high occurrence of osteoporosis and osteopenia in our cohort can be explained by the referral bias where more severe cases are more likely to be referred for treatment, it being a tertiary care institute. Our study highlights that osteoporosis and poor bone mineral health are a significant underrecognized problem in endocrinopathies in both the sexes. In terms of both disease occurrence and severity, patients with T1DM followed by hypergonadotropic hypogonadism and hypogonadotrophic hypogonadism had a greater burden of poor bone mineral health as compared to the more well-recognized PMO and andropause-related bone mineral loss in females and males.
Absolute areal BMD as well as Z score were worst in patients with T1DM in both the sexes at a majority of the sites. This was in spite of these patients being much younger than patients with PMO and andropause. This is especially of concern, as it is likely that they will have much worse bone health and quality of life later in life once they reach the ages comparable to that seen in patients with PMO and andropause in this study. A significantly lower BMI may have contributed to the lower BMD in patients with T1DM due to the trophic effect of mechanical loading of bone on BMD.  This is supported by the observation that the significant differences in areal BMD at different sites among the study groups were lost after adjusting for BMI of the individuals. Low BMD at the median age of early 30s in patients with T1DM may suggest that peak bone mass accrued in these individuals may be lower than the general population. This hypothesis is supported by previous observations of lower BMD in adolescents and adults with T1DM compared to the control population. ,,,, The only study from India evaluating BMD in T1DM reported a significantly lower BMD of the total body and lumbar spine in a cohort of 86 patients 12-45 years of age as compared to age-, sex-, and BMI-matched controls.  This study also noted that T1DM patients had 10% less bone mineral content (BMC) in comparison with the controls.  Impaired bone quality, apart from low BMD, may be another issue with T1DM as evidenced by a meta-analysis showing sixfold increased risk for fracture hip, which was higher than would have been expected on the basis of BMD.  Poor glycemic control has been linked to poor bone health in T1DM. , Hyperglycemia induced hypercalciuria, resulting in negative calcium balance contributes to bone mineral loss in T1DM. , Serum vitamin D was lowest in males with T1DM. In spite of low vitamin D, iPTH was not raised. Functional hypoparathyroidism, along with vitamin D deficiency in T1DM, is believed to contribute to poor bone health in these patients. ,,
After T1DM, the burden of osteoporosis was highest in patients with hypogonadism, which was again much higher than age-related bone mineral loss in women and men (PMO and andropause). In females, the occurrence of osteoporosis was higher in women with hypergonadotropic hypogonadism (Turner syndrome and premature ovarian insufficiency) as compared to those with hypogonadotrophic hypogonadism. Apart from low levels of sex steroids (specifically estrogen), independent detrimental effect of increased circulating levels of FSH in hypergonadotropic hypogonadism may contribute to the increased bone mineral loss in these patients when compared to hypogonadotrophic hypogonadism.  The same could not be assessed in males due to the lack of an adequate number of patients in the male hypergonadotropic hypogonadism group, which is a limitation of this study. Also, due to the small number of patients the cohort of hypogonadotrophic hypogonadism is an heterogenous group of patients, which include those having isolated hypogonadotrophic hypogonadism, along with those having multiple pituitary hormone deficiency (Sheehan syndrome, postpituitary surgery, pituitary tumors, and idiopathic), which is a limitation of this report. However, in spite of the heterogeneous nature of the cohort of patients with hypogonadism in this study, this study highlights that the burden of osteoporosis in patients with hypergonadotropic hypogonadism and hypogonadotrophic hypogonadism is much higher than in patients with age-related bone mineral loss and hence, warrants routine early screening and therapeutic intervention.
Our study showed that the burden of osteoporosis in females and males with GD was similar to that observed in age-related bone mineral loss, viz., PMO in females and andropause in males. It is important to highlight that only 25% and 14.29% of females and males, respectively, with GD had normal BMD. Increased prevalence of vitamin D deficiency, higher circulating levels of thyroid hormones, and loss of trophic effect of thyroid-stimulating hormone (TSH) are believed to contribute to bone mineral loss in GD. ,,
PHPT is a condition, which is well-known to be associated with poor bone mineral health and increased fracture risk. Screening for osteoporosis and steps to improve bone health are routinely taken in these patients (vitamin D supplementation, use of bisphosphonates) before definitive therapy for PHPT. It is important to highlight that the occurrence of osteoporosis was higher in patients with T1DM and hypogonadism even when compared to PHPT, further highlighting the severity of problem in these patients, which frequently goes undetected. It must be highlighted that the differences in areal BMD at different sites among the study groups were lost after adjusting for serum vitamin D levels. Patients with PMO, andropause, and PHPT had higher circulating levels of vitamin D as compared to other endocrinopathies. This may be the result of routine vitamin D supplementation in these patients, as a result of increased awareness for bone health protection in these patients. The high prevalence of vitamin D deficiency in other endocrinopathies is a result of lack of routine vitamin D supplementation in them, and is reflective of generalized vitamin D deficiency in the Indian population. ,, Our study highlights the impact of maintaining adequate serum vitamin D levels on bone health in patients.
The utility of FRAX® tool for fracture risk prediction,  beyond the setting of PMO is not known. Our study showed that FRAX score for fracture risk prediction at the hip and major osteoporotic fracture was not significantly different among males with different etiologies of bone mineral loss. In contrast, in females FRAX risk scores were significantly different among groups and were the highest in women with PMO. FRAX scores in endocrine causes of bone mineral loss were significantly lower in spite of these patients having lower areal BMD and Z scores. This may suggest that FRAX tool may have a limited role in fracture risk prediction in endocrine causes of bone mineral loss.
This study is not exhaustive in the assessment of bone mineral health in endocrinopathies. Bone health was not assessed in patients with Addison's disease, which is a limitation of this report. Also, the impact of treatment on bone health has not been evaluated in this study, which is a limitation. Nevertheless, this study highlights the magnitude and severity of bone mineral loss in endocrine causes of osteoporosis. Patients with T1DM, hypergonadotropic hypogonadism, hypogonadotrophic hypogonadism, and GD are at a significantly higher risk of osteoporosis in later life. Endocrinologists and physicians involved in the care of these patients should carefully evaluate for the risk factors for osteoporosis in these patients routinely. Promotion of physical activities since the diagnosis of disease and adequate routine calcium and vitamin D supplementations are the cornerstone for prevention of impaired bone mineral health in these patients. Till date, treatment of the underlying endocrinopathy has been the primary form of therapy in these patients. Testosterone replacement therapy has been documented to be beneficial in improving BMD in postoperative hypogonadal patients with pituitary tumors.  Growth hormone replacement in adult GHD has been associated with initial transient increase bone resorption and decreased bone mass followed by increased bone formation and increase in bone mass seen beyond 12-18 months of therapy, which has been documented up to 15 years of follow-up. , However, studies are lacking specifically with regard to long-term bone health outcomes in patients with endocrinopathy-induced bone mineral loss. It is of concern that data are lacking with regard to specific pharmacologic interventions (bisphosphonates, teriparatide) intending to improve bone health in these patients. Indirect evidence is there in the form of a population-based cohort study of more than 100,000 individuals from Denmark where no difference was observed in the antifracture efficacy of bisphosphonates and raloxifene between patients with diabetes (T1DM and type 2 diabetes) as compared to nondiabetic controls.  Hence, urgent clinical trials are warranted in patients with the endocrine cause of osteoporosis with an intention of improving bone health and decreasing long-term fracture risk.
The authors are grateful to all the staff of the department of endocrinology for their assistance in meticulous maintenance of records of all patients attending the endocrine services of the department.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]