Management of Skeletal Health in Patients With Asymptomatic Primary Hyperparathyroidism

Abstract

Asymptomatic primary hyperparathyroidism (PHPT) may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. Parathyroid surgery, the definitive treatment for PHPT, has been shown to increase BMD and appears to reduce fracture risk. Current guidelines recommend parathyroid surgery for patients with symptomatic PHPT or asymptomatic PHPT with serum calcium >1 mg/dL above the upper limit of normal, calculated creatinine clearance <60 mL/min, osteoporosis, previous fracture, or age <50 yr. The type of operation performed (parathyroid exploration or minimally invasive procedure) and localizing studies to identify the abnormal parathyroid glands preoperatively should be individualized according to the skills of the surgeon and the resources of the institution. In patients who choose not to be treated surgically or who have contraindications for surgery, medical therapy should include a daily calcium intake of at least 1200 mg and maintenance of serum 25-hydroxyvitamin D levels of at least 20 ng/mL (50 nmol/L). Bisphosphonates and estrogens have been shown to provide skeletal benefits that appear to be similar to parathyroid surgery. Cinacalcet reduces serum calcium in PHPT patients with intractable hypercalcemia but has not been shown to improve BMD. It is not known whether any medical intervention reduces fracture risk in patients with PHPT. There are insufficient data on the natural history and treatment of normocalcemic PHPT to make recommendations for management of this disorder.

Introduction

Primary hyperparathyroidism (PHPT) is a common endocrine disorder with a particular propensity for postmenopausal women, having a prevalence of about 1–3% in this population (1). The skeletal manifestations of PHPT are dramatic and enduring. The earliest known case may be that of a woman whose 7000-yr-old skeleton was uncovered at an Early Neolithic archeological site in Germany. Typical findings of advanced PHPT were found, including radiographic osteopenia, vertebral fractures, bony erosions, and “salt and pepper” skull (2). In 1891, Friedrich von Recklinghausen (3) described a patient with recurrent low-trauma fractures and extensive skeletal fibrosis, lytic expansile bone lesions (“brown” tumors), and bone cysts. It was later thought that this destructive skeletal disease resulted in the development of parathyroid tumors that were observed in autopsies of some of these patients (4). Twenty-one years passed before it was hypothesized that an enlarged parathyroid gland might be the cause of this bone disease, which was called “osteitis fibrosa cystica” (OFC) or “von Recklinghausen's disease of bone” (5). It was not until 1925 that the first parathyroidectomy for this condition was performed in Vienna by Dr Felix Mandl (6) on a streetcar conductor named Albert, who had dramatic improvement in his skeletal symptoms. Soon afterward, the first American parathyroidectomy was performed on Captain Charles Martell, with less fortunate results because of the very advanced nature of his disease and the mediastinal location of this parathyroid adenoma. Subsequent surgery for hyperparathyroidism on other patients in Europe and the United States was associated with improvement in skeletal disease, confirming the concept that the parathyroid glands secreted a substance that was toxic to bones, and that removal of the offending gland could at least partially reverse the bone disease. Skeletal complications are now a recognized consequence of PHPT, although the pattern of bone disease that has evolved as hyperparathyroidism has been detected and treated earlier.

The skeletal manifestations of advanced or “classical” PHPT are the result of long-standing parathyroid hormone (PTH) elevation with hypercalcemia. This may present clinically as generalized or focal bone pain, fragility fractures, or localized swelling of bone. 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 brown tumors of bones, which are nonneoplastic focal areas of extensive bone resorption with fibrous replacement (7). Brown tumors may appear in any part of the skeleton but are seen particularly in the ribs, clavicles, pelvis, and mandible. Patients with multiple brown tumors have sometimes been suspected of having metastatic bone disease (8). When surgically excised, these tumors are typically composed of soft friable red-brown material; histologically there is an accumulation of giant cells in a fibrovascular stroma with cystic spaces and foci of hemorrhage. Rarely, diffuse osteosclerosis is seen in patients with PHPT (9).

Since autoanalyzers for biochemical screening became available in the 1970s, PHPT is usually diagnosed and treated long before the development of OFC. About 80% of PHPT in Western countries is now identified by finding mild persistent or intermittent hypercalcemia on routine laboratory testing in patients without well-defined skeletal symptoms (10). Some patients with normal serum calcium, normal serum 25-hydroxyvitamin D (25-OH-D), and high PTH levels are being detected in the evaluation of osteoporosis. These patients have been classified as having “normocalcemic PHPT,” a disorder associated with skeletal involvement that may represent the earliest form of PHPT (11). Patients with PHPT and skeletal disease usually come to clinical attention in 1 of 2 ways: (1) when low bone mineral density (BMD) is measured or a fracture occurs in a patient with known PHPT or (2) when PHPT is detected in the course of evaluating a patient with known osteoporosis. This is a review of the skeletal consequences of asymptomatic PHPT in patients with and without parathyroid surgery, with a focus on the medical management of those who do not have surgery.