Patients with parathyroid disease can have important musculoskeletal problems. Hypoparathyroidism can cause subcutaneous calcifications, tetany, muscle cramps, and paresthesias, but also myopathies and an ankylosing spondylitis-like back disease. Hypoparathyroidism can occur in systemic lupus erythematosus caused by antiparathyroid antibodies. Patients with hyperparathyroidism may develop bone disease with cysts, erosions, and deformities. They can also develop pseudogout, gout, myopathies, and tendon ruptures.
Parathyroid diseases can be associated with important musculoskeletal problems. These problems vary from well-recognized bone diseases to rare complications. This review addresses the joint, bone, and soft-tissue problems that can occur in patients with hyperparathyroidism and hypoparathyroidism. Parathyroid hormone (PTH) works in conjunction with vitamin D to regulate the total body calcium. PTH has dual actions, both anabolic and catabolic, on the skeleton. PTH provides a powerful mechanism for controlling extracellular calcium and phosphate concentrations. Moreover, it exerts a potent influence in the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the proximal tubules of the kidneys.
The absence of PTH or resistance to PTH by the target organs, especially bones and kidneys, results in low serum ionized calcium, high serum phosphate, and decreased 1,25-dihydroxycholecalciferol. Such a low serum calcium level affects the central and peripheral nervous system, skeletal muscles, and myocardium and can be manifested by neuromuscular irritability, depression, neuropsychiatric manifestations, convulsions, paresthesias, muscle cramps, tetany, prolonged QT intervals, and cardiac failure.
Deficient PTH secretion has postsurgical or idiopathic causes. Idiopathic causes are further categorized into congenital or acquired. Congenital hypoparathyroidism is a condition in which the person is born without parathyroid tissue. Patients usually have no family history of the disease. The acquired form of the disease typically arises because the immune system developed antibodies against the parathyroid tissues. In response to this, the parathyroid stops synthesizing and secreting PTH. The authors discuss this acquired form of the disease in this article.
Hypoparathyroidism usually starts insidiously, with slowly increasing episodic symptoms dominated by increased musculoskeletal irritability. The main symptoms, such as muscle cramps, stiffness, tetany, and paresthesias, may enter the differential diagnosis of the rheumatic diseases. There may be subcutaneous nodules caused by soft-tissue calcification. Although hypoparathyroidism is not uncommon, the diagnosis is often missed because of its unusual clinical manifestations. The mechanism underlying these skeletal changes in hypoparathyroidism is not well defined. The associated musculoskeletal syndromes are subsequently described.
Ankylosing Spondylitis-like Diseases or Diffuse Idiopathic Skeletal Hyperostosis
The skeletal abnormalities of hypoparathyroidism are caused by calcification, which can simulate ankylosing spondylitis with clinical signs, including morning stiffness, gait, and posture. Sacroiliitis is not expected, although it is the earliest manifestation in most patients with ankylosing spondylitis. There may be sacroiliac sclerosis, but not erosions. The patterns of syndesmophytes in patients with hypoparathyroidism can resemble those of ankylosing spondylitis with origin from the vertebral margin and preserved disc space, but more often there is also involvement of the posterior paraspinal ligament. The syndesmophytes reported have been predominantly present in the thoracic and upper lumbar region. Bone density is generally increased in hypoparathyroidism. The syndesmophytes observed have been different from osteophytes of degenerative axial arthritis in that the latter osteophytes spread horizontally before curving up and there is reduction in the disc space. In some cases, these spinal changes are associated with bony proliferation about the pelvis, hip, and long bones, and soft-tissue and tendon calcifications. Although sacroiliac joints are generally spared, periarticular ossification has been recorded in this location. The preservation of sacroiliac joints, HLA B-27 negativity, as well as less significant involvement of the anterior intervertebral ligament does not fit with the diagnosis of ankylosing spondylitis. The pain does not disappear despite taking immunosuppressive agents and nonsteroidal antiinflammatory drugs, but many resolve completely with treatment by calcitriol.
Serum calcium may need to be included in the diagnostic work-up of patients with inflammatory back pain, especially if they present with atypical features as previously described. It is important to differentiate hypoparathyroid-related spondylitis from ankylosing spondylitis because the management for the two disorders is different. In fact, some of the drugs used for ankylosing spondylitis, such as bisphosphonates, may worsen hypocalcemia.
The mechanism underlying these skeletal changes in hypoparathyroidism is not well defined. Decreased intestinal calcium absorption caused by a defect in the action of 1,25-dihydroxyvitamin D (1,25[OH] 2D) has been suggested to play a role in a controlled study of paravertebral ligamentous ossification.
Spinal changes in hypoparathyroidism have also been described to be similar to those in diffuse idiopathic skeletal hyperostosis (DISH) ( Fig. 1 ), which is characterized by ossification of the anterior longitudinal ligament, of the spine, and various extraspinal ligaments, but is rarely reported before the 50 years of age. Okazaki and colleagues suggested that the ossifying diathesis of paravertebral ligaments, which is the origin of DISH, might be initiated or aggravated by hypoparathyroidism.
Systemic Lupus Erythematosus and Rheumatoid Arthritis
Systemic lupus erythematosus (SLE) is known to potentially affect any organ system, and hypoparathyroidism has been found to occur in 4.0% to 5.7% of patients with SLE compared with 1.0% in the general population. Hypoparathyroidism is often diagnosed first or simultaneously but one recent case had SLE diagnosed after known hypoparathyroidism. Attout and colleagues and Nashi and colleagues reported cases of hypoparathyroidism detected incidentally in subjects suffering from SLE. They proposed that hypoparathyroidism is underestimated because it is poorly manifested clinically. Hypocalcemia can be precipitated by certain aggravating factors, such as corticosteroid treatment or vitamin D deficiency.
Although acute hypocalcemia typically gives symptoms and signs of musculoskeletal irritability, chronic hypocalcemia usually gives mild symptoms and can even be asymptomatic. Despite the possible lack of outward manifestations, hypocalcemia may be a significant health risk due to prolongation of the QT interval and the consequent risk of sudden death. These cases raise the question of whether periodic calcium and phosphate screening should be routine care for patients with SLE.
For some time, autoimmunity has been implicated in the pathogenesis of hypoparathyroidism and in a subset of patients with this disease antiparathyroid antibodies can be demonstrated. A mechanistic link has been drawn between these antibodies and hypoparathyroidism by the demonstration that some antiparathyroid antibodies are able to interfere with secretion of parathyroid hormone and some are directly cytotoxic to bovine parathyroid tissue. However, not all antiparathyroid antibodies have a demonstrable physiologic effect. Recently, antibodies against the parathyroid calcium-sensing receptor were found to be significantly more prevalent in subjects with hypoparathyroidism than in normal controls: 49.0% versus 13.3%.
The association between hypoparathyroidism and rheumatoid arthritis (RA) is rare. Edmons and colleagues reported the case of a female subject with longstanding RA and Sjogren syndrome who had a subclinical hypocalcemia. Salvador and colleagues also reported a case. The latter subject, with a previous history of isolated primary hypoparathyroidism, after several years of follow-up, developed a clinical picture suggestive of palindromic rheumatism and, subsequently, a seropositive erosive RA. There is recent evidence of a generalized T-cell activation of peripheral lymphocytes in patients with hypoparathyroidism.
Neuromyotonia, Myopathy, and Rhabdomyolysis
Hypocalcemia caused by hypoparathyroidism has been associated with neuromyotonia (NMT), myopathy, and rhabdomyolysis. Zambelis and colleagues presented a patient with hypoparathyroidism with clinical and electrophysiological findings of neuromyotonia. The patient had the typical clinical findings of hypoparathyroidism. On the other hand, the patient also showed clinical findings typical of NMT: stiffness, paresthesias, and delayed relaxation following voluntary muscle contraction ( pseudomyotonia ) without visible myokymia. The myokymia and NMT are caused by hyperexcitability of motor nerves and hypocalcemia provokes spontaneous motor unit discharges by lowering the excitability threshold of peripheral nerve axons.
Myopathy is well recognized in hypocalcemia associated with osteomalacia, but the serum creatine kinase (CK) is normal. The association between hypocalcemia and a raised serum CK concentration has been reported in hypoparathyroidism but is not widely recognized. In some reports, the CK level varies inversely with the serum calcium concentration. The combination of rash and raised CK can raise the possibility of dermatomyositis, but this can be excluded by biopsy and resolution of these features with treatment of the hypocalcemia. Barber and colleagues illustrated the importance of checking the serum calcium in patients with muscular symptoms and the clinical value of effective treatment of hypocalcemia.
Hypocalcemia caused by hypoparathyroidism or nonparathyroid disease may, as noted above, be associated with elevated serum levels of the muscle enzymes, and in some patients the enzyme activity may be markedly increased. Akmal reported a case of rhabdomyolysis associated with hypocalcemia caused by idiopathic hypoparathyroidism. The mechanisms of the elevated muscle enzyme activity in patients with hypocalcemia are not well understood. Regardless of the mechanisms, the elevated serum muscle enzymes in patients with hypocalcemia particularly caused by hypoparathyroidism should be recognized and treated appropriately.
Subcutaneous calcifications may be seen in the course of hypoparathyroidism, especially about the hips and shoulders. The deposits are generally asymptomatic, although painful calcific periarthritis is reported in this condition, perhaps caused by depression of serum calcium levels. Primary hypoparathyroidism with adhesive capsulitis of the shoulder in the same subject was reported by Harzy and colleagues in a father and daughter. Other patients with hypoparathyroidism have had calcific periarthritis and enthesopathy
Calcification of the basal ganglia occurs in some patients with hypoparathyroidism and is commonly referred to as Fahr syndrome . Although they may be associated with choreoathetosis or a Parkinsonian syndrome, such calcifications may also be asymptomatic.
Both an acquired demyelinating neuropathy and hypoparathyroidism have been found in 2 subjects with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin (POEMS) syndrome. Autoimmune polyendocrine syndrome type 1(APS-1) often includes hypoparathyroidism along with other endocrine deficiencies that can produce musculoskeletal problems. Specific antibodies against NALP5 are found in about half of patients with APS-1 and hypoparathyroidism.
One subject has been reported with hypoparathyroidism developing in a case of cartilage hair hypoplasia (CHH). CHH is a rare autosomal recessive syndrome with severe multisystemic pathology, with immune deficiency, autoimmunity and growth retardation, hair abnormality, panbronchiolitis, hematological symptoms, malabsorption, and chronic diarrhea. CHH is probably linked to autoantibodies directed against the Ca-SR. The Ca-SR is almost ubiquitously expressed in the human body, mainly in the parathyroid cell and the renal tubular cell. In the parathyroid cell, when serum calcium increases, the Ca-SR is activated and inhibits PTH gene expression. Inhibiting mutations in the Ca-SR gene can induce hypercalcemia and hypocalciuria; whereas, activating mutations induce hypocalcemia and hypercalciuria. Symptomatic activating autoantibodies directed against the Ca-SR can be isolated or associated with other immune pathologies.
Pseudohypoparathyroidism and Pseudo Pseudohypoparathyroidism
Pseudohypoparathyroidism (PHP) was first described in 1942 by Albright with a report of a subject with a stocky build, short stature, round facies, brachydactyly, soft-tissue ossifications, and mental retardation a phenotype subsequently known as Albright Hereditary Osteodystrophy. Albright’s subject also had hypocalcemic seizures and resistance to parathyroid hormone, thus the condition was termed pseudohypoparathyroidism . Albright’s hereditary osteodystrophy comprises a distinctive constellation of developmental and skeletal defects consisting of obesity; short, stocky physique; round face; brachydactyly; subcutaneous ossification; and endocrine dysfunction, such as multiple hormone resistance and mental retardation. In most of the reports regarding pseudo pseudohypoparathyroidism (PPHP), metacarpal shortening is observed in the first, fourth, and fifth digits ( Fig. 2 ); metatarsal shortening shows predilection for the first and fourth digits. Shortening of the distal phalanx of the thumb is also common. Similar brachydactyly without hypocalcemia has been described as PPHP. This specific pattern of shortening of the bones in the hand may be useful in distinguishing PPHP from other unrelated syndromes in which brachydactyly occurs, such as familial brachydactyly, Turner syndrome, and Klinefelter syndrome.