Von Recklinghausen was the first to describe the characteristic bone disease that later proved to be the result of hypefarathyroidism. The first to describe the association of bone disease and parathyroid neoplasia was Askanazy, who in 1904 studied a woman with pain in the extremities and spontaneous fractures.1 At autopsy, she was found to have both the generalized osteitis fibrosa cystica described earlier by von Recklinghausen and an "incidental" tumor lateral to the thyroid gland. Three years later, Erdheim studied several patients who had died with severe osteomalacia and correctly concluded the bone disease was due to marked parathyroid hyperplasia.2 The global assimilation of calcium metabolism and the inter-relationship with parathyroid hormone was provided by Fuller Albright.3 He provided data to link changes in parathyroid hormone to fluctuations in serum calcium levels, described hypefarathyroidism due to diffuse hyperplasia of all the parathyroid glands, and explained the physiologic action of parathyroid hormone on bones.4 From these seminal observations, the concept that parathyroid tumors were capable of causing skeletal abnormalities evolved.
Primary hyperparathyroidism was once believed to be a rare disease and often was not diagnosed until patients developed symptoms and signs of advanced disease. However, the routine use of multichannel chemical blood screening has resulted in increased detection of this disease. There now appear to be 25 cases of primary hyperparathyroidism per 100,000 people in the United States, and the incidence increases markedly in elderly individuals.5 Approximately 50,000 new cases present annually. Today, only 20% of patients have nephrolithiasis. In a current series, 5%-15% of patients have associated bony abnormalities. Many asymptomatic patients who do not undergo surgery appear to have progression of disease, but approximately one quarter will have some disease progression.6
Orthopedic surgeons occasionally operate on a patient with a fracture who has primary hyperparathyroidism. High circulating levels of parathyroid hormone induced by hyperparathyroidism "sucks" the calcium out of the bone. This low density of the bone predisposes it to a pathologic fracture, similar to fractures seen in osteoporosis.7 Surgical cure of hyperparathyroidism leads to a prompt and substantial increase in bone density at the lumbar spine and femoral neck, thereby reducing the risk of fracture, as would any postoperative increase in strength and coordination.8
Patients often require parathyroidectomy for definitive management. When presenting with a fracture requiring surgical treatment, the question is which operation should be performed first? In our experience, simultaneous surgery is possible, practical, and effective. Working together, the orthopedic and endocrine surgeons can perform botii procedures under one anesthetic and thereby decrease anesthetic exposure, length of hospital stay, costs, and improve the outcome of the orthopedic procedure.
Figure 1 : Case 7. Radiographs taken at initial presentation (A and B). The patient presented with right knee pain and instability following prior knee replacement and patellar realignment procedure. Revision TKA with a constrained prosthesis and simultaneous parathyroidectomy were performed (C).
It is therefore important for the orthopedic surgeon to be aware of primary hyperparatiiyroidism, its mode of presentation, diagnosis, and orthopedic implications.
A 66-year-old woman presented with spontaneous right knee pain of 1 7 years' duration. She had initially been treated with nonsteroidal anti-inflammatory medications and had voluntarily lost 85 lbs, with some relief of her symptoms.
A right total knee arthroplasty (TKA) was performed 10 years later, following which the patient developed patellar subluxation. She underwent revision surgery 3 months earlier, associated with a patellar realignment procedure. Although she reportedly continued to experience pain and problems with the knee, she did not seek follow-up for another 6 years when she presented to our institution with marked instability of her knee (Figure 1).
Surgical revision of her prosthesis to a constrained prosthesis was recommended. During preoperative preparation, her serum calcium level was 1 1 .5 mg/dL (normal range: 8.4-10.5), and she had an intact parathyroid hormone of 82 (normal range: 1 1-54 pg/mL). A preoperative sestamibi parathyroid imaging suggested a left lower parathyroid abnormality. Simultaneous neck exploration with parathyroidectomy and right knee revision was performed under one anesthetic (Figure 1). At follow-up 37 months postoperatively, the patient had no problems with her operative knee and only mild arthritic symptoms of the contralateral knee and a normal calcium level.
A 72-year-old woman with known primary hyperparathyroidism presented with increasingly severe right thigh pain of 3-4 months* duration. Radiographs revealed a 2X6 cm lytic pertrochanteric lesion of the proximal femur with >75% cortical involvement. The lesion was consistent with a brown tumor (Figure 2A). Her serum calcium level was 1 1 mg/dL, serum phosphorous level was 1.8 mg/dL, and alkaline phosphatase level was 120-140 TU/L.
Sestamibi parathyroid imaging was performed to investigate the location of her parathyroid tumor (Figure 2B). Because severe pain prevented ambulation, and the size and location of the lytic lesion in an area of high stress in the proximal femur placed her at high risk for spontaneous fracture, prophylactic internal fixation of the proximal femur was recommended.9
Internal fixation was performed in coordination with simultaneous neck exploration and parathyroidectomy (Figure 2C). Surgery was uneventful, and her serum parathyroid level on the night of surgery was normal. Subsequently, however, she developed hypocalcemia with serum calcium between 7.5 and 7.6 mg/dL. in association with hungry bone syndrome. This was treated with calcium replacement, and the patient was discharged.
Three weeks later, she remained hypocalcémie, with a serum ionized calcium level of 0.98 mmoI/L (normal range: 1.13-1.32) and a total serum calcium level of 7.1 mg/dL (normal range: 8.4-10.5). Serum parathyroid hormone levels increased from 27 pg/mL immediately following surgery to 219 pg/mL, indicating the development of postoperative secondary hyperparathyroidism.'"
Calcium supplementation was continued and the patient did well for the next 15 months. At that time, she sustained a twisting injury to her contralateral leg resulting in a fracture of die femur. The fracture was treated with intramedullary rod fixation, and the postoperative course was uneventful. Her serum calcium level at that time was 8.8 mg/dL, and her parathyroid level was 25 pg/mL. The patient continued to do well and was normocalcemic with no new fractures over the next 4 years.
A 75-year-old woman with a 3-year history of primary hyperparathyroidism presented with increasing pain and disability due to degenerative arthritis of both knees despite conservative treatment over the preceding 2 years. At initial orthopedic evaluation, a spontaneous pathologic fracture of the proximal fibula was noted (Figures 3A and 3B). Her serum calcium level was 9.6 mg/dL and intact serum parathyroid hormone level was 98 pg/rnL.
Figure 2: Case 2. Radiograph of a 72-year-old woman with known primary hyperparathyroidism and thigh pain reveals a 2x3 cm lytic lesion of the proximal femur consistent with a brown tumor (A). The patient underwent sestamibi scan for parathyroid adenoma localization (B) and prophylactic internal fixation of the proximal femur and simultaneous parathyroidectomy (C).
Due to the increasing pain and disability from the arthritis of her knees, she underwent bilateral staged TKA, performed 3 months apart (Figures 3C and 3D). Simultaneous parathyroid exploration was performed concurrently with one of her knee surgeries. A 2×2 cm parathyroid adenoma was removed.
Surgeries and postoperative course were uneventful. She continues to do well 6 years postoperatively, with normal calcium and parathyroid hormone levels.
A total of 1-2 kg of calcium is present in the average adult, and >98% is in the skeleton (Figure 4). In the blood, 40% of the calcium is protein bound and 50% is free. The concentration of free calcium ions, averaging 4.8 mg/dL, influences many cellular functions and is subject to tight hormonal control, especially through parathyroid hormone. The main source of calcium is dietary intake. It is absorbed from the gastrointestinal tract when epithelial cells lining the small intestine are stimulated by vitamin D. The kidney also is involved in the process of calcium hemostasis. Urinary calcium excretion in normal adults with average calcium intake ranges between 100 and 400 mg/day. The amount of calcium in the urine is small compared to that filtered by the glomeruli because the rate of reabsorption of the filtered calcium is high. Reabsorption occurs predominantly in the proximal tubule (60%) and Henle's loop (25%). Parathyroid hormone causes tubular cells to reabsorb calcium. It also is responsible for stimulating the renal parenchymal cell to hydroxylate vitamin D into its active form, 1,25-dihydroxy vitamin D.11
Calcium can be absorbed from the bone but requires the stimulation of vitamin D and parathyroid hormone. The calcium of the mineral phase at the surface of the crystals is in equilibrium with that in the extracellular fluid, but only a minor fraction of the total pool (approximately 0.5 %) is exchangeable. At low levels of vitamin D or high concentrations [Ca2+]X[PO43- ], bone reabsorption also is decreased. The extracellular pools of Ca2+, PO43-, Mg2+ are in constant equilibrium with bone. In normal adults, extracellular fluid calcium efflux to bone (bone absorption) and influx from bone (bone resorption) are each approximately 4-8 mg/kg of body weight/day, a composite of passive exchange and active transport by bone cells. Bone cells can participate in regulation of extracellular fluid mineral concentration by two mechanisms, specifically osteoblastic absorption and osteolytic exchange of minerals between extracellular fluid and bone.12
Primary hyperparathyroidism results from excess production and secretion of parathyroid hormone from one or more parathyroid glands. It results from an abnormal "set point" of one or more parathyroid glands, and parathyroid hormone is secreted inappropriately relative to the level of serum ionized calcium.13 This condition can occur in genetic syndromes, including multiple endocrine neoplasia types 1 and 2A and isolated familial primary hyperparathyroidism.14 However, most cases occur sporadically without a known genetic predisposition. With the exception of a positive family history, the only known risk factor for primary hyperparathyroidism is a history of irradiation to the head or neck in childhood.15
Primary hyperparathyroidism should be distinguished from secondary and tertiary hypoparathyroidism. In these latter conditions, the parathyroid glands respond to an abnormal host environment in which mineral metabolism is altered, usually because of renal failure or an abnormality in gastrointestinal absorption.16 In chronic renal failure, secondary hyperparathyroidism often coexists with osteomalacia and osteoporosis as part of a spectrum of renal osteodystrophy.
Figure 3: Case 3. Radiographs of the right knee of a 75-year-old woman with a 3-year history of hyperparathyroidism reveal Chondrocalcinosis and a healing spontaneous pathological fracture of the proximal fibula (A). Preoperative standing AP radiographs reveal severe medial compartment arthritis of both knees with varus deformity and Chondrocalcinosis (B). A healed right fibular fracture also is demonstrated. Postoperative radiographs following staged bilateral TKA performed concurrently with parathyroidectomy (C and D).
In primary hyperparathyroidism, microscopic findings of fibrous replacement of normal bone marrow result in classic osteitis fibrosa cystica, which in the past occurred in 10%-25% of patients. Histologically, the pathognomonic features are a reduction in the number of trabeculae. an increase in the giant multinucleated osteoclasts (osteoclastosis) in scalloped areas on the surface of the bone (Howship's lacunae), and a replacement of the normal cellular and marrow elements by fibrous tissues (fibrosa). The total number of osteoblasts also is increased; this is directly related to the increased serum alkaline phosphatase. Osteitis fibrosa cystica is now uncommon, although hyperparathyroidism may be long-standing.17
The symptoms and signs of 100 consecutive patients with primary hyperparathyroidism treated by the authors are listed in the Table. Symptoms often are nonspecific. Vague symptoms such as decreased energy, dyspepsia, changes in mental status, myalgias, and arthralgias are so common in the general population that it is impossible to be certain that they can be attributed to primary hyperparathyroidism in a given patient,18 However, the signs of primary hyperparatiiyroidism are more likely attributable to the patient's endocrinopathy and include renal disease (eg, nephrolithiasis and nephrocalcinosis) and orthopedic findings.
Prior to the wide use of laboratory screening, patients with hyperparathyroidism often presented with advanced disease characterized by renal calculi, diffuse bone pain in combination with characteristic radiographic findings, and dementia resulting from hypercalcemia. Peptic ulcers and pancreatitis also were noted. Due to the increased use of laboratory screening tests, most patients are diagnosed earlier, while they are mildly symptomatic or have evidence of osteopenia.19 The natural history of untreated primary hyperparathyroidism has been an area of interest. Once patients develop symptoms and signs, they require surgical exploration, as there is no effective long-term medical therapy.20,21 Utiger8 suggested virtually all patients with biochemically confirmed primary hyperparathyroidism should undergo surgical treatment.8
Symptoms and Signs of Primary Hyperparathyroidism in 100 Consecutive Patients
Bone disease in hyperparathyroidism may present as bone pain. Nonspecific arthralgias involving all joints in the hand or sometimes centered in die proximal interphalangeal joints also are reported. The etiology of these nonspecific arthralgias is unknown, but they usually remit after corrections of the underlying disorder. Other complications of primary hyperparathyroidism include gout and pseudogout. Musculoskeletal manifestations of hyperparathyroidism include laxity of tendons and ligaments as well as tendon avulsion and rupture. Ligamentous laxity commonly affects the sacroiliac joints, acromioclavicular joints, and spine, whereas tendon rupture is most common in the quadriceps and patellar tendons.22
The diagnosis of primary hyperparathyroidism is relatively straightforward. Most patients have an elevated total and ionized serum calcium level. Alkaline phosphatase is elevated in some patients, and a low serum phosphate level often is noted. Current parathyroid hormone assay techniques are sensitive and specific, and an intact serum parathyroid hormone level should be measured in all patients with an elevated serum calcium level.
In the hypercalcemia setting in the absence of primary hyperparathyroidism, the parathyroid hormone level usually is suppressed. However, in primary hyperparathyroidism, the parathyroid hormone level is either elevated or at least inappropriate in relation to the serum calcium level.
In addition, to rule out the rare occurrence of familial hypocalciuric hypercalcemia, a 24-hour urinary excretion of calcium should be obtained. If the 24hour urinary excretion of calcium is high or even in the normal range, familial hypocalciuric hypercalcemia is essentially ruled out. In summary, the biochemical diagnosis of primary hyperparathyroidism includes measurement of total and ionized serum calcium levels, intact parathyroid hormone, and a 24-hour urinary excretion of calcium.
The radiographic features of primary hyperparathyroidism reflect the skeletal alterations that accompany abnormal mineral homeostasis.23 The biochemical changes of primary hyperparathyroidism include hypercalcemia, hypophosphatemia, and increased renal excretion of calcium and phosphate. These biochemical alterations accompany osteoclastic resorption and osteoblastic ossification.
The most common radiographic abnormalities in patients with primary hyperparathyroidism are osteopenia and subperiosteal bone resorption.24 Other findings include bone sclerosis, brown tumors (evidenced as areas of radiolucency, particularly in the long bones), Chondrocalcinosis, soft-tissue calcification, vascular calcification, and occasionally patchy or diffuse areas of increased bone density (osteosclerosis).25 Radiographic evidence of bone disease in hyperparathyroidism also may include pathologic fractures or bone cysts.26
Figure 4: Calcium stores in the body.
Clinical manifestations and a diagnosis of primary hyperparathyroidism may occur before the development of radiographic signs. In most patients in whom the condition is discovered by noting an incidental serum calcium elevation, routine radiographic studies fail to show specific changes.27
Improved techniques are now available for monitoring bone mineral density. Computed tomography and quantitative digital radiography of the spine provide reproducible quantitative estimates (within a few percent) of spinal bone density. Similarly, cortical bone density in the extremities can be quantified by single-photon densitometry. Serial measurements with these techniques provide early evidence of progressive osteopenia. Most studies indicate cortical rather than trabecular bone tends to be lost selectively in hyperparathyroidism.22 Imaging for hyperparathyroidism remains controversial. Sestamibi has become the preferred isotope for parathyroid scintigraphy.2830 Outpatient parathyroidectomy is now a common procedure.3
Although hyperparathyroidism may result in either bone resorption or bone formation, bone resorption usually dominates. Periarticular bone resorption, the most characteristic finding, usually is classified as subperiosteal, subchondral, trabecular, endosteal, intracortical, subligamentous, and subtendinous. Subperiosteal resorption is the classic and pathognomonic radiographic sign of hyperparathyroidism.32,33 It may occur at any site in the body although the hands and feet are commonly involved. Acro-osteolysis (resorption of phalangeal tufts) also may be present. It is most frequently identified along the radial aspects of the middle phalanges of the index and long fingers. In the hands and feet, this resorption may mimic rheumatoid arthritis. Initially, the outer surface of bone develops a lacy irregular outline. With progression of the disease, the subperiosteal cortical surface becomes fuzzy, ragged, and irregularly spiculated in appearance. Erosions with reactive bone formation may involve the terminal tufts of the fingers and bare areas of the interphalangeal joints. Fine-detail magnification views of the hands increase the accuracy of the radiographic detection of bone résorption and demineralization.27
The skull is the second most commonly affected site. Trabecular resorption is most often seen in the diploic space of the skull, resulting in indistinctness of the inner and outer tables producing a characteristic "salt and pepper" appearance radiographically.34 Confluent resorption of cortical bone also manifests in the distal clavicles. Resorption of trabecular bone contributes to the diffuse osteopenia of hyperparathyroidism.
Figure 5: Diagnosis of hyperparathyroidism in the orthopedic patient.
Other sites of subperiosteal resorption include the medial aspects of the proximal tibiae, femora, and humeri. Erosions also may involve the proximal medial aspect of long bones and the lamina dura of the mandible. Loss of the lamina dura of the teeth is less specific but can be considered a special form of subperiosteal resorption. Demineralization of the teeth is evidenced as loss of die lamina dura.33
Bone resorption in subchondral locations is most often seen at major articulations in the axial skeleton, particularly the sacroiliac joints, sternoclavicular joints, acromioclavicular joints, symphysis pubis, and discovertebral junction.27,35 Osteoclastic resorption of the cortex and trabeculae occurs beneath the cartilaginous surfaces and results in "pseudowidening" of joint space. In these regions, subchondral erosions may cause weakening and collapse of subchondral bone. Sacroiliac joint involvement may mimic ankylosing spondylitis.7·36 In the spine, resorption at the interface between disk and vertebral body may mimic a disk-space infection. Structural weakening of the vertebral bodies can permit herniation into the disk space (Schmorl's nodes). Schmorl's nodes are sometimes widespread in die spines of patients with hyperparathyroidism.
Bone resorption also may occur at intracortical and endosteal locations, leading to cortical striations and localized defects, respectively, on the inner bone surface. Cortical striations are nonspecific and may be seen in any metabolic bone disease with high bone turnover. Endosteal resorption may simulate that seen with a marrow packing disorder, such as multiple myeloma. Intracortical and endosteal erosion is almost always accompanied by the more characteristic subperiosteal resorption.27
In more severe cases, large areas of confluent resorption cause macroscopic cysts, hence, the name cystica. The cysts, when walled with fibrous tissue, unmineralized bone, and areas of hemorrhage, are known as brown tumors because of the hemosiderin deposition. Brown tumors, or osteoclastomas, are composed mostly of osteoclasts and appear as well-defined lytic lesions.37 Either the axial or appendicular skeleton may be involved. These brown tumors usually involve the shaft and, less commonly, the ends of the long bones of the limbs, ribs, jaw, skull, and rarely the hands or feet. They are large lytic lesions formed by confluence of many cysts that expand the cortex of the bone and are surrounded by a thin rim of periosteal bone. The bone lesions, including brown tumors, heal rapidly after successful parathyroidectomy. After resection of parathyroid adenomas, the lesions may become sclerotic and may mimic blastic metastasis.38
Subligamentous and subtendinous resorption classically occur at the inferior margin of the clavicle, the insertion of the plantar aponeurosis and Achilles tendon on the calcaneus, the ischial tuberosities of the pelvis, the tuberosities of the humerus, and the femoral trochanters.27
Chondrocalcinosis is apparent in up to 13% of patients with primary hyperparathyroidism. Like brown tumors, Chondrocalcinosis is seen in both primary and secondary hyperparathyroidism, but is more common in the primary form. Magnified views of the hands to evaluate for bone resorption often reveal calcification in the triangular fibrocartilage of the wrist. An erosive arthropathy (usually asymptomatic) of the hands, wrists, and shoulders may occur in patients with hyperparathyroidism.
These erosions simulate the appearance of rheumatoid arthritis but are located slightly farther from the joint margin and have a shaggy irregular contour. They occur more often on the ulnar aspect of the metacarpal head compared to the radial predilection typical of rheumatoid arthritis. Likewise, they more often involve the distal interphalangeal joints while sparing the proximal interphalangeal joints, a pattern opposite to that found in rheumatoid arthritis.39 The joint space is preserved in hyperparathyroid arthropatiiy. Erosions of the shoulder occur in periarticular and intra-articular locations. It is theorized that osseous erosions probably result from collapse of softened subchondral bone at sites of mechanical pressure with subsequent traumatic synovitis. Secondary osteoarthritis may follow.
The diagnosis of hyperparathyroidism should rarely by missed by the orthopedic surgeon. When a patient presents with a pathologic fracture, routine serum calcium should be obtained. If there is evidence of elevated serum calcium or any of the pathognomonic findings of primary hyperparathyroidism on plain radiographs, total and ionized calcium and an intact parathyroid hormone levels should be obtained to make the diagnosis (Figure 5).
When patients require surgical treatment for an orthopedic condition and also need surgery for hyperparathyroidism, the procedures can be safely performed simultaneously. Simultaneous parathyroidectomy corrects die underlying endocrinopathy, thereby improving the outcome of the orthopedic procedure. In addition, these procedures can easily be performed simultaneously under one anesthetic and thereby minimize cost and length of hospitalization.
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Symptoms and Signs of Primary Hyperparathyroidism in 100 Consecutive Patients