Original Article
Skeletal Effects of Primary Hyperparathyroidism: Bone Mineral Density and Fracture Risk

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Abstract

Parathyroid hormone (PTH) is associated with anabolic and catabolic skeletal effects that vary according to the kinetics of serum levels and the type of bone. The anabolic effects are manifested in patients with a periodic rapid transient rise in serum PTH, as seen with daily subcutaneous injection of PTH(1–34) and PTH(1–84) in the treatment of osteoporosis. These patients have an increase in bone mineral density (BMD), particularly at skeletal sites with a high trabecular component, such as the lumbar spine, and a reduction in fracture risk. The catabolic effects are typified in patients with primary hyperparathyroidism (PHPT) who have chronic persistently elevated PTH levels. Patients with long-standing PHPT have a reduction in BMD, particularly at predominately cortical skeletal sites, such as the one-third radius, with relative preservation of BMD at the lumbar spine. Some but not all studies have reported an increase in fracture risk with PHPT. Because many patients with PHPT are postmenopausal women at risk for osteoporosis owing to estrogen deficiency, BMD and fracture risk may be a result of multiple factors with variable effects on bone remodeling. The skeletal effects of normocalcemic PHPT have not yet been fully characterized, but may not be the same as hypercalcemic PHPT.

Introduction

Classical primary hyperparathyroidism (PHPT), characterized by long-standing parathyroid hormone (PTH) elevation with hypercalcemia, is associated with a bone disease called “osteitis fibrosa cystica” (OFC) (1). The clinical manifestations are generalized or focal bone pain, fragility fractures, and localized bone swelling. The radiographic findings of OFC include subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, “salt-and-pepper” appearance of the skull, and localized radiolucent areas owing to brown tumors—benign focal areas of bone resorption with fibrous replacement (2). The most common sites for brown tumors are the ribs, clavicles, pelvis, and mandible, although they may appear in any part of the skeleton and are sometimes suspected of being metastatic bone disease (3). Brown tumors are composed of friable red-brown fibrous tissue with supporting vasculature with cystic spaces and focal areas of hemorrhage. Bone pain and swelling may occur when the brown tumor extends to the periosteum. Generalized osteosclerosis has been reported in some patients with PHPT (4).

In modern times, classical PHPT with OFC is rarely encountered in world regions where blood chemistry panels that include calcium measurement are part of routine health screening. PHPT is now commonly recognized before the development of obvious skeletal symptoms. In Western countries, approx 80% of patients with PHPT are identified by laboratory tests showing mild persistent or intermittent hypercalcemia followed by the finding of an inappropriately elevated PTH level (5). With the increasing use of PTH measurements in the screening of patients with osteoporosis and suspected metabolic bone disease, patients with high PTH levels, normal serum calcium, and normal serum 25-hydroxyvitamin D (25-OH-D) are being recognized. These patients have been classified as having normocalcemic PHPT, a clinical condition that may represent, for at least some patients, an early stage of hypercalcemic PHPT (6). Regardless of how PHPT comes to clinical attention, an understanding of potential adverse skeletal effects may help to guide physicians in the management of this disease.

Section snippets

Skeletal Effects of PTH at the Molecular and Cellular Levels

PTH exerts dual catabolic and anabolic skeletal effects (Fig. 1) by binding to its transmembrane G-protein–coupled peptide type 1 receptor (PTH1R) in cells of the osteoblast lineage and activating different signaling cascades (7). The catabolic effects are manifested in the development of severe osteoporosis and OFC in patients with classical long-standing PHPT, whereas the anabolic effects prevail in patients treated with daily subcutaneous PTH for osteoporosis. The catabolic effects of PTH

Bone Remodeling and Microarchitecture With PHPT

There are important differences in the skeletal effects of excessive PTH levels in patients with PHPT compared with those associated with estrogen deficiency in women with postmenopausal osteoporosis (PMO). Patients with PHPT typically have high bone remodeling, as assessed by bone turnover markers, compared with controls (13), but bone resorption and formation remain in balance; in contrast, women with PMO have high bone remodeling with an imbalance of bone resorption in excess of formation.

Bone Mineral Density in PHPT

The pattern of bone loss measured by dual-energy X-ray absorptiometry (DXA) in patients with PHPT is consistent with reports of bone histomorphometry and bone microarchitecture. Bone mineral density (BMD) is typically lowest at the one-third (33%) radius, a skeletal site that is predominately cortical bone. By DXA, BMD is relatively well preserved at the lumbar spine, which has a large component of trabecular bone, and intermediate at the hip, which is a mixture of cortical and trabecular bone (

Fracture Risk in PHPT

There is a robust correlation between BMD and fracture risk in women (28) and men (29) without PHPT. In patients with long-standing symptomatic PHPT, overt skeletal disease, including low BMD and fractures, is common (30). Much less is known of the relationship between BMD and fracture risk with PHPT that is mild and asymptomatic (31). Cortical thinning and increased cortical porosity in PHPT might be expected to reduce bone strength; however, this effect could be offset, at least in part, by

Normocalcemic PHPT

As early as 1991, it was hypothesized by Parfitt et al (39) that hypercalcemic PHPT may be preceded by a phase of PTH elevation without hypercalcemia, thus explaining the abnormalities on BMD testing often observed at the time of diagnosis. When PTH levels are measured in the course of an evaluation for secondary causes of osteoporosis, some patients are found to have an elevated PTH with normal total and ionized serum calcium, normal serum 25-OH-D, normal creatinine, and no identifiable cause

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