Bone Disease in Primary Hyperparathyroidism

Bone disease in severe primary hyperparathyroidism (PHPT) is described classically as osteitis fibrosa cystica (OFC). Bone pain, skeletal deformities and pathological fractures are features of OFC. Bone mineral density is usually extremely low in OFC, but it is reversible after surgical cure. The signs and symptoms of severe bone disease include bone pain, pathologic fractures, proximal muscle weakness with hyperreflexia. Bone involvement is typically characterized as salt-and-pepper appearance in the skull, bone erosions and bone resorption of the phalanges, brown tumors and cysts. In the radiography, diffuse demineralization is observed, along with pathological fractures, particularly in the long bones of the extremities. In severe, symptomatic PHPT, marked elevation of the serum calcium and PTH concentrations are seen and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. A new technology, recently approved for clinical use in the United States and Europe, is likely to become more widely available because it is an adaptation of the lumbar spine DXA image. Trabecular bone score (TBS) is a gray-level textural analysis that provides an indirect index of trabecular microarchitecture. Newer technologies, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have provided further understanding of the microstructural skeletal features in PHPT.

Background. Sporadic multiple gland disease in primary hyperparathyroidism occurs in 7 to 33 % of cases. The absence of specific risk factors, low sensitivity of imaging methods, and low efficiency of bilateral neck exploration and intraoperative monitoring of parathyroid hormone indicate the complexity of the diagnosis and treatment of this disease’s form. Aim of the research. To analyze the results of surgical treatment of multiple lesions of the parathyroid gland in primary and secondary hyperparathyroidism. Methods. There was retrospective study, which included 100 observations of surgical treatment for primary and secondary hyperparathyroidism in the thoracic department of Irkutsk Regional Clinical Hospital from May 2018 to September 2019. The main point was to identify the frequency of surgical treatment outcomes in patients with multiple parathyroid lesions. As part of the study, potential predictors of multiple gland disease in primary hyperparathyroidism were analyzed. Results. Multiple gland disease in primary hyperparathyroidism occurs in 29 % of cases and causes persistence of the disease (p ≤ 0.01). Signs of multiple gland disease in primary hyperparathyroidism include the level of ionized calcium, parathyroid hormone (p ≤ 0.05), creatinine level and glomerular filtration rate (p ≤ 0.01). A negative result of intraoperative monitoring correlates with persistence of primary hyperparathyroidism in multiple lesions (χ2, p ≤ 0.05). Selective parathyroidectomy is associated with persistence of hyperparathyroidism in multiple lesions (χ2, p ≤ 0.05), while total parathyroidectomy is associated with remission of the disease (χ2, p ≤ 0.05). We did not find a statistically significant relationship between the results of surgical treatment for morphology of the parathyroid glands (χ2, p > 0.1). Conclusion. Multiple gland disease is the main cause of persistence of primary hyperparathyroidism. This form of the disease corresponds to lower levels of calcium, parathyroid hormone, and kidney function. Persistence factors have been established: removal of less than four parathyroid glands and a negative result of intraoperative monitoring of parathyroid hormone. Bilateral neck exploration does not reduce the incidence of disease persistence.

Parathyroid hormone (PTH) may be anabolic at trabecular bone and catabolic in cortical bone. As many regions of the skeleton contain both types of bone, the effects of PTH deficiency or excess may be difficult to evaluate using bone densitometry, a technique that integrates the cortical and trabecular compartments of bone. We asked the following questions: 1) Is the higher bone mineral density (BMD) in postsurgical hypoparathyroidism due to higher cortical, not trabecular, bone? 2) Is age-related bone loss slowed in patients with postsurgical hypoparathyroidism? 3) Is lower BMD in primary hyperparathyroidism the result of deficits in cortical, not trabecular, bone? BMD of the lumbar spine, proximal femur, distal radius, and femoral midshaft was measured by postero-anterior (PA) scanning, while bone mineral content (BMC) of the third lumbar vertebra was measured by lateral scanning using dual x-ray absorptiometry in 10 women, ages 64.6 +/- 3.2 yr, with postsurgical hypoparathyroidism and in 25 women, ages 68.7 +/- 1.6 yr, with primary hyperparathyroidism. Measurements were repeated 4.7 +/- 0.6 yr later in 8 patients with hypoparathyroidism and 4.0 +/- 0.4 yr later in 20 age-matched controls. Data were expressed as z scores (SD, mean +/- sem) derived from 405 postmenopausal women. In patients with hypoparathyroidism, bone mass z score of the third lumbar vertebra (vertebral body plus posterior processes) was higher than zero by PA scanning (1.26 +/- 0.58 SD, P < 0.05) and lateral scanning (1.04 +/- 0.60 SD, P = 0.1), and higher at the trabecular-rich vertebral body (1.02 +/- 0.47 SD, P = 0.07) and predominantly cortical posterior processes (0.98 +/- 0.66 SD, P = 0.1) determined by lateral scanning. The BMD z scores were higher than zero at the femoral neck (0.89 +/- 0.48 SD, P = 0.09), but not at the femoral midshaft (0.45 +/- 0.60, NS) and distal radius (0.04 +/- 0.51, NS). During follow-up, femoral neck BMD decreased in controls but not in patients with hypoparathyroidism (slope, -0.00818 +/- 0.00496 g/cm2/year vs. 0.00907 +/- 0.00583 g/cm2/year, respectively, P = 0.06). There was no change in lumbar spine BMD in either group. In 25 women with primary hyperparathyroidism, there were no deficits in BMD at the third lumbar vertebra (vertebral body plus posterior processes) by PA or lateral scanning. By lateral scanning, BMC was increased at the vertebral body (0.64 +/- 0.31 SD, P < 0.01) and reduced at the posterior processes (-0.65 +/- 0.26 SD, P < 0.05). BMD was lower at the midshaft of the femur (-0.82 +/- 0.37 SD, P < 0.05) and at the distal radius (-0.68 +/- 0.20 SD, P < 0.01), but not at the femoral neck (-0.08 +/- 0.20 SD, NS). Longitudinal data were unavailable in hyperparathyroid patients. In summary, trabecular bone is increased by both PTH deficiency and excess. Cortical bone loss is slowed by PTH deficiency and accelerated by PTH excess so that suppression of PTH may reduce age-related bone loss and the risk of fracture. Assessment of BMD in PTH deficiency and excess requires the separate study of cortical and trabecular bone.

FRI0503 USING BONE MINERAL DENSITY VERSUS THE RATIO OF BODY MASS INDEX TO BONE MINERAL DENSITY TO PREDICT FRACTURE RISK IN HYPERTHYROIDISM

Primary hyperparathyroidism (PHPT) is a common endocrinopathy, predominantly caused by a single parathyroid adenoma that is responsible for the excessive secretion of parathyroid hormone (PTH)-the hallmark of disease. Excess of this hormone causes remarkable changes in bone metabolism, including an increased level of bone remodeling with a predominance of bone resorption. Those changes lead to deterioration of bone structure and density, especially in cortical bone. The main treatment for PHPT is surgical removal of the adenoma, which normalizes PTH levels and terminates the progression of bone disease and leads to its regeneration. However, because not all the patients are suitable candidates for surgery, alternative therapies are needed. Current non-surgical treatments targeting bone disease secondary to PHPT include bisphosphonates and denosumab. Those antiresorptives prevent further bone loss, but they lack the ability to regenerate already degraded bone. There is ongoing research to find targeted drugs capable of halting resorption alongside stimulating bone formation. This review presents the advancements in understanding the molecular mechanisms responsible for bone disease in PHPT and assesses the efficacy of new potential therapeutic approaches (e.g., allosteric inhibitors of the PTH receptor, V-ATPase, or cathepsin inhibitors) aimed at mitigating bone loss and enhancing bone regeneration in affected patients.

A Structural Approach to Renal Bone Disease

To examine factors, in addition to bone mineral density (BMD), such as the common calcium-sensing receptor (CASR) gene polymorphisms, associated with vertebral fracture (VFx) risk in primary hyperparathyroidism (PHPT). A cross-sectional analysis of 266 Caucasian PHPT seen as outpatients. Serum calcium (sCa) phosphate metabolism parameters were measured. BMD was assessed by dual-energy X-ray absorptiometry (expressed as Z-score) at lumbar spine (Z-LS) and femoral neck, morphometric VFx by radiograph, and CASR A986S/R990G genotypes by PCR amplification and genomic DNA sequencing. Fractured patients (n=100, 37.6%) had lower sCa (10.8±0.7 mg/dl) and Z-LS BMD (-1.0±1.44), higher age (61±10 years), and prevalence (51%) of ≥1 S alleles of the CASR A986S single-nucleotide polymorphism (SNP; AS/SS), than those not fractured (n=166, 11.2±1.0 mg/dl, -0.57±0.97, 58±13 years, and 38% AS/SS, respectively, P<0.05 for all comparisons). Logistic regression, with VFx as dependent variable, showed independent risks associated with increased age (OR 1.03, 95% CI 1.01-1.06, P=0.006), decreased sCa (OR 1.86, 95% CI 1.28-2.7, P=0.001), and Z-LS BMD (OR 1.4, 95% CI 1.12-1.7, P=0.002) and presence of AS/SS (OR 1.8, 95% CI 1.1-2.9, P=0.05). The presence of two out of three factors (age ≥58 years, sCa <10.8 and Z-LS BMD≤-1.0, and AS/SS genotype) gave an overall OR of 4.2 (95% CI 2.25-7.85, P<0.0001). In PHPT, VFx is associated positively with age, negatively with sCa and spinal BMD, and presence of at least one copy of the CASR A986S SNP.

THE UTILITY OF TBS-ADJUSTED BMD T-SCORE IN THE DISCRIMINATION OF THE MAJOR OSTEOPOROTIC FRACTURES IN THE POSTMENOPAUSAL WOMEN OF THE ROTTERDAM AND THE OSTEOLAUS STUDIES

12 Bone Disease in Primary Hyperparathyroidism

Relationship between Urinary Calcium and Bone Mineral Density in Patients with Calcium Nephrolithiasis

The significance of high bone density in children

ObjectivesEmerging evidence has indicated a role for pharmacologic agents in the primary prevention of osteoporotic fracture, but have not yet been systematically reviewed for meta-analysis. We conducted a meta-analysis to evaluate the efficacy of pharmacologic interventions in reducing fracture risk and increasing bone mineral density (BMD) in postmenopausal women with osteopenia or osteoporosis but without prevalent fragility fracture. MethodThe Medline, EMBASE, and CENTRAL databases were searched from inception to September 30, 2019. Only randomized placebo-controlled trials evaluating postmenopausal women with −1.0 > bone mineral density (BMD) T-score > −2.5 (low bone mass) and those with BMD T-score ≤ −2.5 (osteoporosis) but without baseline fractures, who were receiving anti-osteoporotic agents, providing quantitative outcomes data and evaluating risk of vertebral and/or non-vertebral fragility fracture at follow-up. The PRISMA guidelines were followed, applying a random-effects model. The primary endpoint was the effect of anti-osteoporotic regimens in reducing the incidence of vertebral fractures. Secondary endpoints were percentage changes in baseline BMD at the lumbar spine and total hip at 1 and 2 years follow up. ResultsFull-text review of 144 articles yielded, 20 for meta-analysis. Bisphosphonates reduced the risk of vertebral fracture (pooled OR = 0.50, 95%CIs = 0.36–0.71) and significantly increased lumbar spine BMD after 1 year, by 4.42% vs placebo (95%CIs = 3.70%–5.14%). At the hip, this value was 2.94% (95%CIs = 2.13%–3.75%). Overall results of limited studies for non-bisphosphonate drugs showed increased BMD and raloxifene significantly decreases the risk of subsequent clinical vertebral fractures. ConclusionThe bisphosphonates are efficacious and most evident for the primary prevention of osteoporotic vertebral fractures, reducing their incidence and improving BMD in postmenopausal women with osteopenia or osteoporosis.

The topic of increased risk of bone fracture associated with thiazolidinediones (TZD) treatment first drew international attention when a higher rate of fractures in women with diabetes treated with rosiglitazone was reported in the A Diabetes Outcome Program Trial (ADOPT)1. Subsequently, a number of clinical trials and observational studies addressing this issue have been reported and most of them have confirmed the increased risk of fracture in elderly women with type 2 diabetes mellitus treated with both rosiglitazone and pioglitazone. A recent report by Bilik et al. provided additional insight into the association between TZD treatment and bone fractures in patients with type 2 diabetes mellitus, showing that postmenopausal women taking TZD and the subset of men taking both loop diuretics and TZD were at increased risk for fractures2. Nevertheless, the results of currently available reports have still been inconclusive. For example, rosiglitazone and pioglitazone were reported to show comparable risk of fractures in some studies, whereas others have found a difference in the risk of fracture between these two drugs. Does the risk for fracture with TZD extend to men and to younger patients? Is it also applicable in Asian populations? TZD exert many metabolic actions by interaction with peroxisome proliferator-activated receptor (PPAR)γ, which is expressed in a number of tissues and directly regulates gene expression involved in adipogenesis, glucose homeostasis and inflammation responses. Most importantly, PPARγ plays an important role in adipocyte differentiation, as shown by studies in which overexpression of PPARγ in fibroblast cell lines initiates adipogenesis, and embryonic stem (ES) cells and embryonic fibroblasts from PPARγ deficient mice could not differentiate into adipocytes. A series of experiments, in which TZD were given to rodents, showed adverse effects of TZD against bone metabolism. Both rosiglitazone and pioglitazone have been shown to consistently cause bone loss accompanied by decreased osteoblast activity and bone formation, and often by an increase in bone marrow adiposity. Although the effects of TZD administration on bone resorption were somewhat inconsistent and less compelling, increased bone resorption was often concomitant with decreased bone mass, particularly in aged animals given rosiglitazone. TZD are likely to have suppressive effect on bone formation and their stimulatory effects on bone resorption might be enhanced when given to aged animals (Figure 1). Effect of thiazolidinedione on bone metabolism. The activation of peroxisome proliferator-activated receptor (PPAR)γ by thiazolidinedione (TZD) stimulates adipogenesis, thereby regulating a number of cellular signaling pathways involved in bone metabolism. Differentiation of mesenchymal stem cells into osteoblasts is affected by preferential differentiation of mesenchymal stem cells into adipocytes. Reduced osteoblastogenesis likely indirectly modulates osteoclastogenesis. Altered maturation of mesenchymal stem cells, in concert with humoral factors, shifts the balance between bone formation and resorption. At a cellular level, a number of signaling pathways mediated by TZD might indirectly influence bone metabolism (Figure 1). Amelioration of insulin resistance by TZD lowers circulating levels of insulin and amylin, each of which is anabolic to osteoblasts. Activation of PPARγ in adipocytes influences expression and production of an array of adipocytokines, many of which have been suggested in the regulation of bone metabolism. Rosiglitazone is reported to decrease circulating insulin-like growth factor (IGF)-1 level, which is one of the crucial factors in the regulation of osteoblast differentiation and proliferation. Decrease in IGF-1 in bone might be detrimental to bone mass through the inhibition of osteoblast formation. Thus, many humoral factors, under the regulation of TZD, are likely to modulate bone metabolism concurrently with improvement of insulin resistance. A report of increased risk of fracture with TZD treatment in the ADOPT study1 was subsequently followed by clinical studies addressing the effects of TZD on bone mineral density (BMD). In the Health, Aging, and Body Composition (ABC) prospective observational study, each year of TZD (troglitazone, pioglitazone and/or rosiglitazone) use by older (age range 70–79 years) diabetic women was associated with a statistically significant increase in the annualized rate of whole-body bone loss (0.6–1.2% per year)3. Another observational study examining BMD of 32 men with type 2 diabetes treated with rosiglitazone for 16 months showed a three to sixfold increase in the rate of bone loss in the spine, hip and proximal femur, compared with 128 matched men with type 2 diabetes mellitus not taking rosiglitazone4, despite the fact that no effect was observed on BMD in the male diabetes group (n = 32) taking TZD in the Health ABC study. According to the results from ADOPT, a 4-year study of glycemic durability of monotherapy, the rate of fracture in diabetic patients randomized to receive rosiglitazone was higher in women, but not in men, than that in patients randomized to receive either metformin or glyburide1. A pooled analysis of fracture incidence from randomized trials of pioglitazone, with the maximum duration of exposure to pioglitazone of 3.5 years collectively including 15,000 subjects (8100 with pioglitazone and 7400 with comparator), also showed an increase of limb fractures in women, but not in men, receiving pioglitazone. In contrast, a prospective, randomized, controlled study in Japan with the duration of 2.5–4 years that included 587 Japanese type 2 diabetes patients did not show any difference in the risk of fracture between groups receiving or not receiving pioglitazone, even in the older women5. More recently, a meta-analysis, in which 10 randomized controlled trials involving 13,715 participants and two observational studies involving 31,679 participants were used to determine the risk of fractures associated with TZD therapy, was reported. Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% CI 1.18–1.79, P < 0.001). A significant increase in the risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; P < 0.001), but not among men (OR 1.00, 95% CI 0.73–1.39, P = 0.98), was shown in five randomized controlled trials. The two observational studies showed an increased risk of fractures associated with rosiglitazone and pioglitazone. It was thus concluded in that study that long-term TZD use doubles the risk of fractures among women with type 2 diabetes mellitus, without a significant increase in the risk of fractures among men with type 2 diabetes mellitus6. Although it is important to acknowledge the fact that many of the studies described here are observational and were carried out in European and American populations, and that fractures were not a prespecified end-point, menopausal status was not considered and patients studied were relatively young (age range 55–60 years); an increased risk of fractures, at least in older women, is regarded as a class effect of TZD in a limited ethnic population at this time. Generally, type 2 diabetes mellitus is associated with an increased risk of fractures, with the risk increasing with longer duration of disease. Recent meta-analysis of observational studies has confirmed an increase in fracture risk in patients with type 2 diabetes mellitus, particularly of the hip, proximal humerus and foot. Risk factors that also contribute to increased fracture in diabetic patients include number of falls, insulin use, functional disability and impaired vision. The Health ABC study showed the increase in fracture risk not only in type 2 diabetes patients, but also in patients with elevated fasting plasma glucose3. Thus, it is not always simple to clinically discriminate risk of fracture induced by TZD use and to set up a prospective study to investigate the relationship between risk of fractures and TZD in patients with type 2 diabetes mellitus. Considering the undisputed reward provided by the use of TZD, particularly in patients with higher risk for cardiovascular diseases, tentativeness for TZD use in such patients might be excessive and lack an appropriate balance between usefulness and disadvantage. Nevertheless, it should be required to assess risk factors of fracture, such as age, sex, bodyweight, menopausal status and family history of fracture, particularly for patients being considered for treatment with TZD. In particular, it would be prudent, in the light of a fact that female patients are generally more sensitive to this class of drugs, to discreetly prescribe lower doses of TZD in younger women who are expected to take them over long periods.

Patients with hyperparathyroidism (HPT) generally display reduced bone mass due to excessive PTH activity. The effect of parathyroidectomy on bone mass changes in different types of HPT, however, is not well understood. Bone mineral density (BMD) was measured in the distal radius, total body, femoral neck, and lumbar spine by dual energy x-ray absorptiometry in four groups of patients with different hyperparathyroid conditions: primary symptomatic HPT (n = 54), primary asymptomatic (mild) HPT (n = 24), HPT associated with hemodialysis (n = 20), and HPT associated with renal transplant (n = 30). Subsets of patients with primary symptomatic HPT (n = 52), HPT associated with hemodialysis (n = 19), and HPT associated with renal transplant (n = 15) underwent parathyroidectomy, and bone density was measured longitudinally for 3 yr. Patients with primary asymptomatic (mild) HPT did not undergo surgery and were followed prospectively. Before surgery, all groups showed a greater reduction of bone mineral density in cortical bone (distal radius) than in predominantly trabecular bone (lumbar spine). In primary symptomatic HPT, the BMD z-score of the distal radius was -1.80 +/- 0.21 (+/-SEM), and the corresponding figures for the total body, femoral neck, and lumbar spine were -0.60 +/- 0.15, -0.54 +/- 0.14, and -0.53 +/- 0.18 compared with those of an age- and sex-matched reference group. In renal HPT BMD z-scores were -2.51 +/- 0.38 (hemodialysis patients) and -2.83 +/- 0.43 (renal transplant patients) for the distal radius and between -0.81 and -1.46 for the other measured sites. After parathyroidectomy, BMD increased by 1-8% at all sites in patients with primary symptomatic HPT and HPT associated with renal transplant. The largest increase in bone mass was observed in patients with HPT associated with hemodialysis, in whom the improvement amounted to 7-23%. In patients with primary HPT and HPT associated with hemodialysis, this increase in bone density resulted in virtual recovery from their preoperative bone loss. The majority of patients with asymptomatic primary HPT disease (n = 21) maintained their bone density during the follow-up period and have not shown evidence of increases in serum calcium or PTH levels, but three patients followed conservatively underwent parathyroidectomy due to progressive deterioration of BMD. We conclude that, regardless of the etiology, a large proportion of HPT patients show reduced bone density. In patients with primary symptomatic HPT and patients with HPT associated with hemodialysis, bone density increases after parathyroidectomy to an extent that largely restores the preoperative bone loss. However, no anabolic effect of parathyroidectomy on bone mass was observed in patients with HPT associated with renal transplant, probably because of their immunosuppressive therapy.

SummaryThis prospective study aimed to determine the risk factors and the 10-year probability of osteoporotic fracture in Southern Chinese men. The findings show substantial population differences in fracture incidence and risk prediction compared to the FRAXTM model, and the addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men.IntroductionClinical risk factors with or without bone mineral density (BMD) measurements are increasingly recognized as reliable predictors of fracture risk. Prospective data on fracture incidence in Asian men remain sparse. This prospective study aimed to determine the risk factors and the 10-year absolute fracture risk in Southern Chinese men.MethodsThis is a part of the Hong Kong Osteoporosis Study. One thousand eight hundred ten (1,810) community-dwelling, treatment-naive men aged 50 years or above were evaluated. Baseline demographic characteristics, clinical risk factors and BMD were recorded. Ten-year risk of osteoporotic fracture was calculated using Cox proportional hazards models.ResultsThe mean age of subjects was 68.0 ± 10.3 years. After a mean follow-up period of 3.5±2.9 years (range 1 to 14 years), 37 incident low-trauma fractures were recorded. The incidence for all osteoporotic fractures and hip fractures was 635/100,000 and 123/100,000 person-years, respectively. The most significant predictors of osteoporotic fracture were history of fall (RR 14.5), femoral neck BMD T-score < −2.5 (RR 13.8) and history of fracture (RR 4.4). Each SD reduction in BMD was associated with a 1.8 to 2.6-fold increase in fracture risk. Subjects with seven clinical risk factors and BMD T-score of −1 had an absolute 10-year risk of osteoporotic fracture of 8.9%, but this increased to 22.7% if they also had a femoral neck BMD T-score of −2.5.ConclusionsThese findings show substantial population differences in fracture incidence and risk prediction. The addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men.