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Skeletal Lesions in Primary Hyperparathyroidism
CLINICAL INVESTIGATION
Skeletal Lesions in Primary Hyperparathyroidism Qiang Yang, PhD,* Peng Sun, MD,# Jianmin Li, PhD,* Zhiping Yang, PhD,* Xin Li, PhD,* Zhenfeng Li, PhD,* Jun Yan, PhD,* Ka Li, PhD* and Luqiang Wang, MD*
Abstract: Background: Osteitis fibrosa cystica (OFC), a relatively rare skeletal disorder caused by excess parathyroid hormone, is often misdiagnosed as a neoplasm. A summary of the diagnostic procedures and treatment protocols, especially the indications for orthopedic surgery, is helpful to avoid overtreatment. Methods: Eight patients from the Orthopedic Department of Qilu Hospital of Shandong University diagnosed with OFC caused by primary hyperparathyroidism were treated, and the clinical manifestations, biochemical and radiography examination findings, surgeries and prognoses were recorded. Results: All cases (5 female and 3 male) were admitted to our department with the complaint of bone pain (5/8) or fracture after mild trauma (3/8). Biochemical screening revealed hypercalcemia and high parathyroid hormone of varying levels. Two cases were misdiagnosed as primary bone lesion and metastasis. All cases were treated with parathyroidectomy and experienced spontaneous and progressive regression of the boney disease. Four cases underwent orthopedic surgery. Bone biopsies were necessary to exclude malignant tumors, especially with orthopedic procedures. Conclusions: OFC can easily be misdiagnosed in orthopedic patients because of a lack of radiological and histologic specificity. Reaching the correct diagnosis requires a combination of clinical manifestations, routine biochemical screenings, radiographic examinations of bone and parathyroid and bone biopsy. It is generally acknowledged that parathyroidectomy is effective, but orthopedic surgery is sometimes necessary after a correct diagnosis and parathyroidectomy. However, the indications for orthopedic surgery must be strictly controlled to avoid overtreatment. Key Indexing Terms: Osteitis fibrosa cystica; Brown tumor; Primary hyperparathyroidism. [Am J Med Sci 2015;349(4):321–327.]
steitis fibrosa cystica (OFC) is a skeletal disorder that occurs secondary to hyperparathyroidism and is caused by long-term stimulation by excess parathyroid hormone (PTH). The overactivity and proliferation of osteoclasts stimulated by PTH breaks down bone and leads to replacement of bone matrix and thinning of the cortex. The cystic defects can be filled with brown hemosiderin deposits, leading to the term, “brown tumors.”1 This process is not neoplastic but rather a reparative cellular process.2 Brown tumor most commonly presents as a slowly enlarging painful mass that can be locally aggressive, without metastatic potential.3 Primary hyperparathyroidism (PHPT) is most often caused by parathyroid adenoma (80%–85%) with parathyroid carcinoma occurring in less than 0.5% to 4% of cases. Women are more often affected than men, especially postmenopausal
O
From the *Orthopaedic Department, Qilu Hospital of Shandong University, Jinan, China; #Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences. Submitted October 3, 2013; accepted in revised form September 11, 2014. The authors have no financial or other conflicts of interest to disclose. Correspondence: Jianmin Li, PhD, Orthopaedic Department, Qilu Hospital of Shandong University, No. 107 of Wenhuaxi Road, 250012 Jinan, China (E-mail: [email protected]).
The American Journal of the Medical Sciences
women of age 50 to 60 years. The estimated incidence is 2 to 3 cases per 1,000 women and 1 case per 1,000 men, approximately a 3:1 ratio.4 Secondary hyperparathyroidism is caused mainly by chronic kidney disease; hereditary disease is rare and presents mainly in adolescents.5 Asymptomatic hypercalcemia is the most common clinical manifestation of PHPT, occurring in approximately 80% of cases.6 With now common routine biochemical screening, the incidence of the severe form of the skeletal manifestations has decreased in developed countries in recent decades.7 However, because of a delay in seeking medical attention and lack of routine biochemical screening, OFC remains the primary presentation of PHPT in many developing countries.8 OFC is characterized by the presence of subperiosteal resorption in the digits, skull and long bones, diffuse osteopenia and brown tumors.6 In patients with PHPT whose chief complaint is bone pain, the incidence of misdiagnosis is relatively high and results in ineffective therapy.8,9 Surgical overtreatment is unnecessary and causes additional patient trauma. There is no doubt that parathyroidectomy is the first choice in OFC management; however, there is debate about whether orthopedic intervention is also necessary.10–12 The ideal diagnostic and orthopedic therapeutic approach requires further research. The authors describe 8 patients suffering from OFC caused by PHPT in the orthopaedic department. The authors discuss the clinical manifestations, diagnosis, treatment and prognosis.
PATIENTS Eight patients were initially admitted to the orthopaedic department because they presented with bone pain or fracture, and bone diseases were assumed. No family history of parathyroid or thyroid disease and no calcium deficiencies were found in these patients. Patient information included clinical manifestations, preoperative biochemical screening, radiographic evaluations of bone and parathyroid, histologic findings, surgeries and prognosis. Biochemical examinations comprised serum calcium and phosphorus, serum alkaline phosphatase, serum creatinine, serum urea nitrogen and intact PTH. Radiological surveys for bone diseases included plain film radiography, computed tomography (CT), magnetic resonance imaging (MRI) and emission computed tomography (ECT). Plain film radiography or ultrasound of the abdomen was performed to identify kidney or ureteral calculi. Parathyroid radiography consisted of CT, ultrasound or ECT. Bone mineral density (BMD) was not measured because of limited availability. Bone biopsy was performed to exclude malignant tumors. The 8 patients underwent parathyroidectomy. One of the patients was misdiagnosed as having a bone cyst, another 3 patients presented with pathological fracture after minor trauma and 1 was misdiagnosed with a simple fracture. Histologic examinations were performed after parathyroidectomy and orthopedic surgery or biopsies. Changes in the concentrations of serum calcium and PTH were followed after
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parathyroidectomy in all patients. Postoperative hypocalcemia was managed by administering oral calcium and 1,25dihydroxyvitamin D (calcitriol) in addition to calcium gluconate infusion. The mean postoperative follow-up duration was 46.6 months (range, 4–96 months). The postoperative evolution of brown tumors was mainly evaluated by radiography.
RESULTS The 8 cases included 5 (62.5%) women and 3 (37.5%) men with a mean age of 42 years (range, 28–55 years). All cases were admitted to our department with a chief complaint of bone pain or fracture in different sites, and we divided the cases into 2 groups: fracture and nonfracture (Table 1). Five cases (62.5%) were diagnosed with malaise with local bone pain. The average visual analog scale pain score was 5.6 (range, 4–8) preoperatively. One patient was misdiagnosed as having a bone cyst and underwent tumor curettage and allograft bone padding. Recurrence occurred 3 years later when the diagnosis was confirmed, and a parathyroid adenoma was resected. Three cases (37.5%) sought medical attention for pathological bone fracture; all fracture sites were in the lower limbs. Before pathological fracture, all patients reported feeling either no pain or mild discomfort only. One patient was treated as a simple bone fracture and underwent external fixation surgery (1/3), with severe bone pain recurring in the same leg 1 year later. The other 2 cases were treated with open reduction and internal fixation. We identified nephrolithiasis in 5 cases by abdominal plain film radiography (62.5%) with 1 patient also having a severe peptic ulcer and no improvement with proton pump inhibitors. Routine biochemical screening was carried out in all patients (100%) (Table 2). Serum calcium was elevated to varying degrees with a mean concentration of 3.26 mmol/L (range, 2.66–3.72 mmol/L). All cases presented with high alkaline phosphatase levels of 401 to 2,537 U/L with a mean value of 1,002 U/L. The mean PTH value was 1,058 g/mL (range, 99– 2,261 g/mL). All patients initially underwent plain film radiography, with additional CT or MRI after hospital admission (Figures 1A–D). Radiological evaluation demonstrated lytic lesions in not only cortical bone such as the femoral and humeral shaft but also in the cancellous bone such as the pelvic ring, femoral head and vertebrae. The final radiological diagnoses were subjective and included brown tumor (3/8, 37.5%), bone cyst (1/8, 12.5%), giant cell tumor (1/8, 12.5%) or multiple bone metastases (1/8, 12.5%); another 2 cases showed osteolytic lesions without clear results (2/8, 25%). Eight cases (100%) had cervical CT imaging examination (Figure 1E), ultrasound or
TABLE 1. Basic information and clinical manifestations Case Gender Age (yr) Malaise 1 2 3 4 5 6 7 8
F F F F M F M M
55 41 28 54 37 53 30 36
Present Present Present Present Present Absent Absent Absent
parathyroid ECT (Figure 2A), which identified the character of the space-occupying lesions in the parathyroid gland area. Six patients (75%) accepted ECT examination of the entire skeleton, showing diffuse increased radioactive nuclide concentration (Figure 2B). Parathyroidectomy was performed after clear diagnosis in all 8 cases (100%) (Table 3). Intraoperative exploration accurately estimated the tumor size, location and states of invasion, and all tumors were located in the lower thyroid lobes (100%). Intraoperative fast-frozen pathology and routine postoperative pathology of the parathyroid tumors revealed predominantly parathyroid adenoma (Figure 2C) (87.5%), and only 1 case was diagnosed as parathyroid carcinoma (12.5%). Recurrence was observed in 1 patient after the first parathyroidectomy because of residual tumor, and a second surgery was curative. Two patients underwent bone biopsy and 4 patients underwent orthopedic surgery, including 3 pathological fracture cases. All 6 histopathological results after bone processing showed giant cell tissue. After parathyroidectomy, clinical evaluation of brown tumors demonstrated spontaneous regression in all cases but with different regression response patterns. Six months postoperatively, all 5 patients who had suffered from bone pain on admission had their pain resolve after parathyroidectomy. Serum calcium and PTH were monitored after parathyroidectomy. Hypocalcemia commonly persisted and was managed by oral calcium carbonate and calcitriol. Successful diagnosis followed by parathyroidectomy was curative. Four cases underwent orthopedic surgeries; however, 2 cases (50%) were misdiagnosed, delaying the cure of the primary causes by 1 year in 1 case and 3 years in the other.
DISCUSSION OFC is a nonneoplastic lesion caused by chronic stimulation by excess PTH. The over secretion of PTH results in not only the overactivity of osteoclasts but more importantly, an increased proliferation and number of osteoclasts, termed osteoclast cytosis. Normal bone stroma is then replaced by fibrous tissue, hemorrhage, hemosiderin deposition and cystic areas. The hemorrhage and hemosiderin deposition give the tumor a brownish color and thus the term brown tumor.1 PHPT is the most common reason for excess PTH. Parathyroid adenoma predominates and was diagnosed in 87.5% of our patients with only 1 case (12.5%) of parathyroid carcinoma. The reason that women are more often affected is not clear; however, a higher sensitivity to PTH in women, especially menopausal women, may partly explain why more
Bone pain
VAS score
Fracture
Nephrolithiasis
Present Present Present Present Present Absent Absent Absent
5 6 5 4 8 0 0 0
Absent Absent Absent Absent Absent Present Present Present
Absent Present Present Absent Present Present Absent Present
F, female; M, male; PHPT, primary hyperparathyroidism.
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TABLE 2. Biochemical screening results Case SC (mmol/L) SP (mmol/L) 1 2 3 4 5 6 7 8
3.67 3.14 3.36 3.51 3.72 2.66 3.35 3.46
0.65 0.45 0.68 0.73 0.80 0.51 1.00 0.62
Scr (mmol/L)
SUN (mmol/L)
AKP (U/L)
PTH (pg/mL)
102 63 69 56 96 29 81 59
6.20 4.50 4.99 6.51 4.81 3.50 5.45 5.98
732 505 1,002 401 937 1,212 2,537 693
1,165 2,261 605 286 1,653 1,612 786 99
AKP, alkaline phosphatase (15–112 U/L); PTH, parathyroid hormone (15–65 pg/mL); SC, serum calcium (2.0–2.6 mmol/L); SP, serum phosphorus (0.6–1.6 mmol/L); Scr, serum creatinine (44–106 mmol/L); SUN, serum urea nitrogen (2.3–7.8 mmol/L).
women are affected.6 Resendiz-Colosia et al7 reported 22 cases of PHPT with maxillofacial bone OFC, including 20 (90.9%) women and 2 men (9.1%). In our study, the sex difference was not obvious (female:male, 5:3), likely because of the small sample size. Since the 1950s, as biochemical screening became routine in developed countries, skeletal disease related to PHPT has been rarely reported because of early therapy. In contrast, OFC dominates as the main presentation in PHPT in many developing countries. A delay in seeking medical attention and a lack of routine screening may be the principle reasons8; however, these factors alone do not fully explain the differences.13,14 All 8 cases were initially referred to the orthorpaedic department for 2 reasons: malaise with bone pain and fracture after minor trauma. OFC commonly presents as a slowly enlarging painful mass without metastatic potential3; however, a painful mass was rarely seen in these patients. Common sites of OFC are the maxillofacial bone, ribs, clavicle, long bones and pelvic girdle.13 Trabecular bones are spared because PTH
is known to have a protective effect on cancellous bone.15,16 However, in the authors’ experience, there was no obvious difference in the morbidity in the different bone types. All patients (100%) suffered from brown tumors in multiple nonmaxillofacial bones, including both cortical and cancellous bones. The possible explanation for the lack of difference in the morbidity by bone type may be the comprehensive radiography methods used to detect the lesions including CT, MRI and ECT. Regardless of lesion location, the chief symptoms in almost all patients initially presented in the long bones (7/8, 87.5%), especially those of the lower limbs, possibly related to the load function of the lower limbs. The classical radiographic features of OFC are osteopenia, diffuse subperiosteal bone resorption (Figure 3A) and brown tumors.6 Plain film radiograph reveals well-defined lytic lesions without sclerosis and a “salt and pepper” or “ground glass” appearance in the bones of the skull. Abdominal plain films revealed urolithiasis in several of our patients. CT is useful to identify the location, number and extent of the lesions,
FIGURE 1. Plain radiographic film (A) showing multiple lytic lesions in the pelvic ring. CT scan (B) showing boney defects in the acetabulum and pubic ramus with 2-dimensional CT reconstruction (C) and 3-dimensional CT reconstruction (D). The arrow (E) shows a space-occupying lesion in the left parathyroid gland area with the histologic result of parathyroid adenoma after cervical parathyroid CT. Copyright © 2015 by the Southern Society for Clinical Investigation.
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FIGURE 2. Parathyroid ECT (A) showing increased radioactive nuclide concentration in the parathyroid gland area of the lower left thyroid (arrow). Bone ECT (B) showing diffuse increased radioactive nuclide concentration in both the cortical bone of the proximal femur and the cancellous bone of the vertebrae. Photomicrograph showing the histopathology (C) of a parathyroid adenoma (maginification, 10 3 20).
and MRI can differentiate the tissue components of brown tumor based on the contrast of the signal intensity. The presence of hemosiderin deposition and fibrous stroma explains the low intensity on T2-weighted images.17 ECT is helpful to identify intact lesions and shows increased radioactive nuclide in the lytic lesions as a result of the osteoclast overactivity. Parathyroid radiography was performed to confirm the presence of parathyroid tumor in this study, and the authors stress that a single type of radiography examination, such as plain film,
TABLE 3. Information related to the operations Case Fracture Orthopedic surgery Misdiagnosis 1 2 3 4 5 6 7 8
0 0 0 0 0 1 1 1
0 0 0 0 1 1 1 1
0 0 0 0 1 1 0 0
easily leads to misdiagnosis. In this study, 2 cases (25%) were misdiagnosed mainly because local plain film radiography alone was performed, and patients were diagnosed as having a simple fracture and bone cyst. In cases of OFC, a combination of radiography methods is necessary to identify multiple lesions and avoid misdiagnosis. Some authors of this study hold the opinion that brown tumor presents in the late stages of PHPT without correct treatment and leads to increased bone turnover, deterioration of
Parathyroidectomy
Routine pathology
Follow-up (mo)
1 1 1 1 1 1 1 1
Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma carcinoma
14 7 42 83 96 36 91 4
1, present; 0, absent.
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FIGURE 3. Plain radiographic film of the palm (A) showing diffuse subperiosteal bone resorption of the phalanges. Plain film (B) showing lytic lesions in both proximal femurs that were misdiagnosed as bone cyst and were followed with tumor curettage and allograft bone padding (C). Three years later, the lytic lesions had progressed on plain films (D) when the diagnosis of OFC was confirmed.
BMD and increased incidence of bone fracture.18–21 Most densitometry studies support that PTH is catabolic at cortical sites with anabolic effects at cancellous bone sites. Quantitative histomorphometric studies from iliac crest biopsies have revealed a 50% to 60% increase in bone turnover leading to increased bone resorption in PHPT patients.18,19,22 The results of plain radiography are unreliable. Only 3 case in this study, (37.5%), were defined as brown tumors on the basis of plain radiography and biochemical screening, and the others were misdiagnosed. Therefore, information from other sources must be taken into consideration. Bone fracture after minor trauma or spontaneous fracture is a dangerous signal alerting clinicians to underlying bone destruction. With increasing routine biochemical screening, hypercalcemia has been identified as an indicator of the presence of OFC. In this study, all 8 patients presented with hypercalcemia of varying levels. The clinical manifestations caused by hypercalcemia include kidney stones, nausea, peptic ulcers, appetite loss and weight loss, and “bones, stones, abdominal groans and psychic overtones.”23 As more sensitive biochemical screening is used, typical symptoms such as acute pancreatitis and peptic ulcer caused by hypercalcemia are uncommon.24 However, the extent of hypercalcemia may not reflect the severity of the clinical manifestations. Findings show, the serum calcium concentration in 1 patient who suffered severe peptic ulcer was only 3.14 mmol/L. However, the patient with the highest serum calcium (3.67 mmol/L) presented with only mild symptoms. Alkaline phosphatase, which is an index of bone turnover, was often increased in this study. Because of lack of examination service, the 25-hydroxyvitamin D data are absent in this study. However, some studies have proved that a low 25-hydroxyvitamin D level is accompanied by high PTH levels and both interact to increase disease activity in PHPT.25,26 This means that vitamin D deficiency can influence mineral metabolism to cause reduced cortical bone density or strength and vice versa.6,7,27,28 Therefore, vitamin D supplementation is useful in the treatment of OFC. Histologically, the bone disease in PHPT is described as an intensely vascular fibroblastic stroma background for cell populations consisting of rounded mononuclear cells mixed with a number of osteoclast-like multinucleated cells. Hemorrhage and hemosiderin deposition can sometimes also be seen. It is well Copyright © 2015 by the Southern Society for Clinical Investigation.
known that brown tumors exhibit no pathognomonic histologic changes, but the term is an effective way to exclude malignant tumors and metastasis, thus avoiding unnecessary surgery.29,30 Because of a lack of specificity in radiography and histology, making a diagnosis of OFC is not easy. Differentiating between a brown tumor and other tumors, such as giant cell tumor and giant cell reparative granuloma, may be difficult; however, the latter 2 rarely present with diffuse osteoporosis. The multiple lytic lesions seen radiographically are often mistreated as osteosarcoma, metastasis or multiple myeloma. Other differential diagnoses that should be considered include bone cyst, aneurysmal bone cystic, Paget’s disease and ossifying fibroma.31–34 In the authors experience, a correct OFC diagnosis depends on comprehensive clinical examinations. An in-depth medical history is very important including duration of malaise, bone pain or painful mass and details of any fracture. Biochemical screening is also important. Serum calcium and PTH should be examined at the same time because normal serum calcium occurs often in PHPT.30,33 A variety of bone imaging methods in combination with parathyroid radiography are also helpful to make the diagnosis. A bone biopsy before choosing surgery is necessary to exclude malignant bone tumors to avoid misdiagnosis. Parathyroidectomy has been shown to halt bone deterioration, improve BMD and reduce the risk of fracture in PHPT patients.10–12 The procedure also leads to regression of brown tumors.35,36 VanderWalde et al10 reported that patients who underwent parathyroidectomy compared with those who did not had a reduced risk of fracture regardless of age, or calcium or PTH level. Therefore, it is suggested that bone surgery is unnecessary for brown tumors.3,37 For patients with OFC who seek medical attention in orthopedic departments, the choice of treatment strategies is critical, especially when surgery is considered. The authors suggest that a precondition for surgery is a correct diagnosis. Then, surgical interventions can proceed in the following cases: for a large mass with or without severe bone pain, for a persistent aggressive mass, delayed treatment, bone fracture leading to functional disability or a high risk of disability, recurrence after surgery and considering patients’ wishes. Surgical treatments can relieve bone pain and improve quality of life, but parathyroidectomy must be performed before orthopedic surgery, or the orthopedic intervention is pointless
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(Figures 3B–D). In this study, 25% of the patients were misdiagnosed so cure of the primary disease was delayed, and recurrence occurred 1 year later in once case and 3 years later in another. The proportion of patients with OFC undergoing orthopedic surgeries is as high as 50%. Therefore, one must carefully consider the operative indications to avoid misdiagnosis and delayed treatment. Whether bone surgery can improve the regression rate requires large case-control studies to confirm. Not all patients are surgical candidates. The likelihood of parathyroidectomy decreases with increasing age, and the procedure is not recommended in older patients.38 Most studies favor medical therapy and recommend monitoring the serum calcium in the absence of clear and compelling empirical evidence.39,40 The most recent recommended guidelines are as follows: annual serum calcium, annual serum creatinine and bone density study every 1 to 2 years (3 sites).38 Oral calcium and calcitriol supplements are needed to control hypocalcemia. Bisphosphonates are frequently used, and this practice is supported by several clinical trials; however, serum and urinary calcium monitoring are suggested for longtime use.40 For emergency hypocalcemia symptoms, such as muscle spasm, calcium gluconate infusion can be useful. In conclusion, the presence of multisite osteolytic and boney giant cell lesions or fracture after minor trauma is an important clinical sign. A correct diagnosis of OFC alone will not correct the metabolic problems, but it can avoid unnecessary bone resection in most cases. However, if the surgical indications are appropriate for a patient, surgical intervention should be considered. REFERENCES 1. Guney E, Yigitbasi OG, Bayram F, et al. Brown tumor of the maxilla associated with primary hyperparathyroidism. Auris Nasus Larynx 2001;28:369–72. 2. Dogan A, Algun E, Kisli E, et al. Calcaneal brown tumor with primary hyperparathyroidism caused by parathyroid carcinoma: an atypical localization. J Foot Ankle Surg 2004;43:248–51.
12. Vestergaard P, Mollerup CL, Frokjaer VG, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598–602. 13. Boudou P, Ibrahim F, Cormier C, et al. A very high incidence of low 25 hydroxy-vitamin D serum concentration in a French population of patients with primary hyperparathyroidism. J Endocrinol Invest 2006; 29:511–15. 14. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 2001;86:1212–21. 15. Guo CY, Thomas WE, al-Dehaimi AW, et al. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81: 3487–91. 16. Syed Z, Khan A. Skeletal effects of primary hyperparathyroidism. Endocr Pract 2000;6:385–8. 17. Rubin MR, Livolsi VA, Bandeira F, et al. Tc99m-sestamibi uptake in osteitis fibrosa cystica simulating metastatic bone disease. J Clin Endocrinol Metab 2001;86:5138–41. 18. Mosekilde L, Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperparathyroidism. Acta Med Scand 1978;204:97–102. 19. Charhon SA, Edouard CM, Arlot ME, et al. Effects of parathyroid hormone on remodeling of iliac trabecular bone packets in patients with primary hyperparathyroidism. Clin Orthop Relat Res 1982: 255–63. 20. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283–91. 21. Dempster DW, Cosman F, Parisien M, et al. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14:690–709. 22. Eriksen EF, Mosekilde L, Melsen F. Trabecular bone remodeling and balance in primary hyperparathyroidism. Bone 1986;7:213–21. 23. Maina AM, Kraus H. Successful treatment of osteitis fibrosa cystica from primary hyperparathyroidism. Case Rep Orthop 2012;2012:145760.
3. Scott SN, Graham SM, Sato Y, et al. Brown tumor of the palate in a patient with primary hyperparathyroidism. Ann Otol Rhinol Laryngol 1999;108:91–4.
24. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863–75.
4. Kearns AE, Thompson GB. Medical and surgical management of hyperparathyroidism. Mayo Clin Proc 2002;77:87–91.
25. Mishra SK, Agarwal G, Kar DK, et al. Unique clinical characteristics of primary hyperparathyroidism in India. Br J Surg 2001;88:708–14.
5. Marx SJ. Hyperparathyroid genes: sequences reveal answers and questions. Endocr Pract 2011;17(suppl 3):18–27.
26. Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005;257:6–17.
6. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: still evolving? J Bone Miner Res 1997;12:856–62. 7. Resendiz-Colosia JA, Rodriguez-Cuevas SA, Flores-Diaz R, et al. Evolution of maxillofacial brown tumors after parathyroidectomy in primary hyperparathyroidism. Head Neck 2008;30:1497–504. 8. Agarwal G, Mishra SK, Kar DK, et al. Recovery pattern of patients with osteitis fibrosa cystica in primary hyperparathyroidism after successful parathyroidectomy. Surgery 2002;132:1075–83; discussion 1083–1075. 9. Hoshi M, Takami M, Kajikawa M, et al. A case of multiple skeletal lesions of brown tumors, mimicking carcinoma metastases. Arch Orthop Trauma Surg 2008;128:149–54. 10. VanderWalde LH, Liu IL, Haigh PI. Effect of bone mineral density and parathyroidectomy on fracture risk in primary hyperparathyroidism. World J Surg 2009;33:406–11. 11. Rao DS, Wallace EA, Antonelli RF, et al. Forearm bone density in primary hyperparathyroidism: long-term follow-up with and without parathyroidectomy. Clin Endocrinol (oxf) 2003;58:348–54.
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27. Bilezikian JP, Meng X, Shi Y, et al. Primary hyperparathyroidism in women: a tale of two cities–New York and Beijing. Int J Fertil Womens Med 2000;45:158–65. 28. Stein EM, Dempster DW, Udesky J, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone 2011;48:557–61. 29. Al-Gahtany M, Cusimano M, Singer W, et al. Brown tumors of the skull base. Case report and review of the literature. J Neurosurg 2003; 98:417–20. 30. Emin AH, Suoglu Y, Demir D, et al. Normocalcemic hyperparathyroidism presented with mandibular brown tumor: report of a case. Auris Nasus Larynx 2004;31:299–304. 31. Lessa MM, Sakae FA, Tsuji RK, et al. Brown tumor of the facial bones: case report and literature review. Ear Nose Throat J 2005;84:432–4. 32. Martinez-Gavidia EM, Bagan JV, Milian-Masanet MA, et al. Highly aggressive brown tumour of the maxilla as first manifestation of primary hyperparathyroidism. Int J Oral Maxillofac Surg 2000;29:447–9.
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33. Suarez-Cunqueiro MM, Schoen R, Kersten A, et al. Brown tumor of the mandible as first manifestation of atypical parathyroid adenoma. J Oral Maxillofac Surg 2004;62:1024–8.
37. Daniels JS. Primary hyperparathyroidism presenting as a palatal brown tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98: 409–13.
34. Triantafillidou K, Zouloumis L, Karakinaris G, et al. Brown tumors of the jaws associated with primary or secondary hyperparathyroidism. A clinical study and review of the literature. Am J Otolaryngol 2006;27: 281–6.
38. Wu B, Haigh PI, Hwang R, et al. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2010;95:4324–30.
35. Endo I, Matsumoto T. Primary hyperparathyroidism [in Japanese]. Nihon Rinsho 2006;64:1718–23. 36. Arabi A, Khoury N, Zahed L, et al. Regression of skeletal manifestations of hyperparathyroidism with oral vitamin D. J Clin Endocrinol Metab 2006;91:2480–3.
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39. Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94:335–9. 40. Khan A, Bilezikian J. Primary hyperparathyroidism: pathophysiology and impact on bone. CMAJ 2000;163:184–7.
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Skeletal Lesions in Primary Hyperparathyroidism Qiang Yang, PhD,* Peng Sun, MD,# Jianmin Li, PhD,* Zhiping Yang, PhD,* Xin Li, PhD,* Zhenfeng Li, PhD,* Jun Yan, PhD,* Ka Li, PhD* and Luqiang Wang, MD*
Abstract: Background: Osteitis fibrosa cystica (OFC), a relatively rare skeletal disorder caused by excess parathyroid hormone, is often misdiagnosed as a neoplasm. A summary of the diagnostic procedures and treatment protocols, especially the indications for orthopedic surgery, is helpful to avoid overtreatment. Methods: Eight patients from the Orthopedic Department of Qilu Hospital of Shandong University diagnosed with OFC caused by primary hyperparathyroidism were treated, and the clinical manifestations, biochemical and radiography examination findings, surgeries and prognoses were recorded. Results: All cases (5 female and 3 male) were admitted to our department with the complaint of bone pain (5/8) or fracture after mild trauma (3/8). Biochemical screening revealed hypercalcemia and high parathyroid hormone of varying levels. Two cases were misdiagnosed as primary bone lesion and metastasis. All cases were treated with parathyroidectomy and experienced spontaneous and progressive regression of the boney disease. Four cases underwent orthopedic surgery. Bone biopsies were necessary to exclude malignant tumors, especially with orthopedic procedures. Conclusions: OFC can easily be misdiagnosed in orthopedic patients because of a lack of radiological and histologic specificity. Reaching the correct diagnosis requires a combination of clinical manifestations, routine biochemical screenings, radiographic examinations of bone and parathyroid and bone biopsy. It is generally acknowledged that parathyroidectomy is effective, but orthopedic surgery is sometimes necessary after a correct diagnosis and parathyroidectomy. However, the indications for orthopedic surgery must be strictly controlled to avoid overtreatment. Key Indexing Terms: Osteitis fibrosa cystica; Brown tumor; Primary hyperparathyroidism. [Am J Med Sci 2015;349(4):321–327.]
steitis fibrosa cystica (OFC) is a skeletal disorder that occurs secondary to hyperparathyroidism and is caused by long-term stimulation by excess parathyroid hormone (PTH). The overactivity and proliferation of osteoclasts stimulated by PTH breaks down bone and leads to replacement of bone matrix and thinning of the cortex. The cystic defects can be filled with brown hemosiderin deposits, leading to the term, “brown tumors.”1 This process is not neoplastic but rather a reparative cellular process.2 Brown tumor most commonly presents as a slowly enlarging painful mass that can be locally aggressive, without metastatic potential.3 Primary hyperparathyroidism (PHPT) is most often caused by parathyroid adenoma (80%–85%) with parathyroid carcinoma occurring in less than 0.5% to 4% of cases. Women are more often affected than men, especially postmenopausal
O
From the *Orthopaedic Department, Qilu Hospital of Shandong University, Jinan, China; #Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences. Submitted October 3, 2013; accepted in revised form September 11, 2014. The authors have no financial or other conflicts of interest to disclose. Correspondence: Jianmin Li, PhD, Orthopaedic Department, Qilu Hospital of Shandong University, No. 107 of Wenhuaxi Road, 250012 Jinan, China (E-mail: [email protected]).
The American Journal of the Medical Sciences
women of age 50 to 60 years. The estimated incidence is 2 to 3 cases per 1,000 women and 1 case per 1,000 men, approximately a 3:1 ratio.4 Secondary hyperparathyroidism is caused mainly by chronic kidney disease; hereditary disease is rare and presents mainly in adolescents.5 Asymptomatic hypercalcemia is the most common clinical manifestation of PHPT, occurring in approximately 80% of cases.6 With now common routine biochemical screening, the incidence of the severe form of the skeletal manifestations has decreased in developed countries in recent decades.7 However, because of a delay in seeking medical attention and lack of routine biochemical screening, OFC remains the primary presentation of PHPT in many developing countries.8 OFC is characterized by the presence of subperiosteal resorption in the digits, skull and long bones, diffuse osteopenia and brown tumors.6 In patients with PHPT whose chief complaint is bone pain, the incidence of misdiagnosis is relatively high and results in ineffective therapy.8,9 Surgical overtreatment is unnecessary and causes additional patient trauma. There is no doubt that parathyroidectomy is the first choice in OFC management; however, there is debate about whether orthopedic intervention is also necessary.10–12 The ideal diagnostic and orthopedic therapeutic approach requires further research. The authors describe 8 patients suffering from OFC caused by PHPT in the orthopaedic department. The authors discuss the clinical manifestations, diagnosis, treatment and prognosis.
PATIENTS Eight patients were initially admitted to the orthopaedic department because they presented with bone pain or fracture, and bone diseases were assumed. No family history of parathyroid or thyroid disease and no calcium deficiencies were found in these patients. Patient information included clinical manifestations, preoperative biochemical screening, radiographic evaluations of bone and parathyroid, histologic findings, surgeries and prognosis. Biochemical examinations comprised serum calcium and phosphorus, serum alkaline phosphatase, serum creatinine, serum urea nitrogen and intact PTH. Radiological surveys for bone diseases included plain film radiography, computed tomography (CT), magnetic resonance imaging (MRI) and emission computed tomography (ECT). Plain film radiography or ultrasound of the abdomen was performed to identify kidney or ureteral calculi. Parathyroid radiography consisted of CT, ultrasound or ECT. Bone mineral density (BMD) was not measured because of limited availability. Bone biopsy was performed to exclude malignant tumors. The 8 patients underwent parathyroidectomy. One of the patients was misdiagnosed as having a bone cyst, another 3 patients presented with pathological fracture after minor trauma and 1 was misdiagnosed with a simple fracture. Histologic examinations were performed after parathyroidectomy and orthopedic surgery or biopsies. Changes in the concentrations of serum calcium and PTH were followed after
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parathyroidectomy in all patients. Postoperative hypocalcemia was managed by administering oral calcium and 1,25dihydroxyvitamin D (calcitriol) in addition to calcium gluconate infusion. The mean postoperative follow-up duration was 46.6 months (range, 4–96 months). The postoperative evolution of brown tumors was mainly evaluated by radiography.
RESULTS The 8 cases included 5 (62.5%) women and 3 (37.5%) men with a mean age of 42 years (range, 28–55 years). All cases were admitted to our department with a chief complaint of bone pain or fracture in different sites, and we divided the cases into 2 groups: fracture and nonfracture (Table 1). Five cases (62.5%) were diagnosed with malaise with local bone pain. The average visual analog scale pain score was 5.6 (range, 4–8) preoperatively. One patient was misdiagnosed as having a bone cyst and underwent tumor curettage and allograft bone padding. Recurrence occurred 3 years later when the diagnosis was confirmed, and a parathyroid adenoma was resected. Three cases (37.5%) sought medical attention for pathological bone fracture; all fracture sites were in the lower limbs. Before pathological fracture, all patients reported feeling either no pain or mild discomfort only. One patient was treated as a simple bone fracture and underwent external fixation surgery (1/3), with severe bone pain recurring in the same leg 1 year later. The other 2 cases were treated with open reduction and internal fixation. We identified nephrolithiasis in 5 cases by abdominal plain film radiography (62.5%) with 1 patient also having a severe peptic ulcer and no improvement with proton pump inhibitors. Routine biochemical screening was carried out in all patients (100%) (Table 2). Serum calcium was elevated to varying degrees with a mean concentration of 3.26 mmol/L (range, 2.66–3.72 mmol/L). All cases presented with high alkaline phosphatase levels of 401 to 2,537 U/L with a mean value of 1,002 U/L. The mean PTH value was 1,058 g/mL (range, 99– 2,261 g/mL). All patients initially underwent plain film radiography, with additional CT or MRI after hospital admission (Figures 1A–D). Radiological evaluation demonstrated lytic lesions in not only cortical bone such as the femoral and humeral shaft but also in the cancellous bone such as the pelvic ring, femoral head and vertebrae. The final radiological diagnoses were subjective and included brown tumor (3/8, 37.5%), bone cyst (1/8, 12.5%), giant cell tumor (1/8, 12.5%) or multiple bone metastases (1/8, 12.5%); another 2 cases showed osteolytic lesions without clear results (2/8, 25%). Eight cases (100%) had cervical CT imaging examination (Figure 1E), ultrasound or
TABLE 1. Basic information and clinical manifestations Case Gender Age (yr) Malaise 1 2 3 4 5 6 7 8
F F F F M F M M
55 41 28 54 37 53 30 36
Present Present Present Present Present Absent Absent Absent
parathyroid ECT (Figure 2A), which identified the character of the space-occupying lesions in the parathyroid gland area. Six patients (75%) accepted ECT examination of the entire skeleton, showing diffuse increased radioactive nuclide concentration (Figure 2B). Parathyroidectomy was performed after clear diagnosis in all 8 cases (100%) (Table 3). Intraoperative exploration accurately estimated the tumor size, location and states of invasion, and all tumors were located in the lower thyroid lobes (100%). Intraoperative fast-frozen pathology and routine postoperative pathology of the parathyroid tumors revealed predominantly parathyroid adenoma (Figure 2C) (87.5%), and only 1 case was diagnosed as parathyroid carcinoma (12.5%). Recurrence was observed in 1 patient after the first parathyroidectomy because of residual tumor, and a second surgery was curative. Two patients underwent bone biopsy and 4 patients underwent orthopedic surgery, including 3 pathological fracture cases. All 6 histopathological results after bone processing showed giant cell tissue. After parathyroidectomy, clinical evaluation of brown tumors demonstrated spontaneous regression in all cases but with different regression response patterns. Six months postoperatively, all 5 patients who had suffered from bone pain on admission had their pain resolve after parathyroidectomy. Serum calcium and PTH were monitored after parathyroidectomy. Hypocalcemia commonly persisted and was managed by oral calcium carbonate and calcitriol. Successful diagnosis followed by parathyroidectomy was curative. Four cases underwent orthopedic surgeries; however, 2 cases (50%) were misdiagnosed, delaying the cure of the primary causes by 1 year in 1 case and 3 years in the other.
DISCUSSION OFC is a nonneoplastic lesion caused by chronic stimulation by excess PTH. The over secretion of PTH results in not only the overactivity of osteoclasts but more importantly, an increased proliferation and number of osteoclasts, termed osteoclast cytosis. Normal bone stroma is then replaced by fibrous tissue, hemorrhage, hemosiderin deposition and cystic areas. The hemorrhage and hemosiderin deposition give the tumor a brownish color and thus the term brown tumor.1 PHPT is the most common reason for excess PTH. Parathyroid adenoma predominates and was diagnosed in 87.5% of our patients with only 1 case (12.5%) of parathyroid carcinoma. The reason that women are more often affected is not clear; however, a higher sensitivity to PTH in women, especially menopausal women, may partly explain why more
Bone pain
VAS score
Fracture
Nephrolithiasis
Present Present Present Present Present Absent Absent Absent
5 6 5 4 8 0 0 0
Absent Absent Absent Absent Absent Present Present Present
Absent Present Present Absent Present Present Absent Present
F, female; M, male; PHPT, primary hyperparathyroidism.
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TABLE 2. Biochemical screening results Case SC (mmol/L) SP (mmol/L) 1 2 3 4 5 6 7 8
3.67 3.14 3.36 3.51 3.72 2.66 3.35 3.46
0.65 0.45 0.68 0.73 0.80 0.51 1.00 0.62
Scr (mmol/L)
SUN (mmol/L)
AKP (U/L)
PTH (pg/mL)
102 63 69 56 96 29 81 59
6.20 4.50 4.99 6.51 4.81 3.50 5.45 5.98
732 505 1,002 401 937 1,212 2,537 693
1,165 2,261 605 286 1,653 1,612 786 99
AKP, alkaline phosphatase (15–112 U/L); PTH, parathyroid hormone (15–65 pg/mL); SC, serum calcium (2.0–2.6 mmol/L); SP, serum phosphorus (0.6–1.6 mmol/L); Scr, serum creatinine (44–106 mmol/L); SUN, serum urea nitrogen (2.3–7.8 mmol/L).
women are affected.6 Resendiz-Colosia et al7 reported 22 cases of PHPT with maxillofacial bone OFC, including 20 (90.9%) women and 2 men (9.1%). In our study, the sex difference was not obvious (female:male, 5:3), likely because of the small sample size. Since the 1950s, as biochemical screening became routine in developed countries, skeletal disease related to PHPT has been rarely reported because of early therapy. In contrast, OFC dominates as the main presentation in PHPT in many developing countries. A delay in seeking medical attention and a lack of routine screening may be the principle reasons8; however, these factors alone do not fully explain the differences.13,14 All 8 cases were initially referred to the orthorpaedic department for 2 reasons: malaise with bone pain and fracture after minor trauma. OFC commonly presents as a slowly enlarging painful mass without metastatic potential3; however, a painful mass was rarely seen in these patients. Common sites of OFC are the maxillofacial bone, ribs, clavicle, long bones and pelvic girdle.13 Trabecular bones are spared because PTH
is known to have a protective effect on cancellous bone.15,16 However, in the authors’ experience, there was no obvious difference in the morbidity in the different bone types. All patients (100%) suffered from brown tumors in multiple nonmaxillofacial bones, including both cortical and cancellous bones. The possible explanation for the lack of difference in the morbidity by bone type may be the comprehensive radiography methods used to detect the lesions including CT, MRI and ECT. Regardless of lesion location, the chief symptoms in almost all patients initially presented in the long bones (7/8, 87.5%), especially those of the lower limbs, possibly related to the load function of the lower limbs. The classical radiographic features of OFC are osteopenia, diffuse subperiosteal bone resorption (Figure 3A) and brown tumors.6 Plain film radiograph reveals well-defined lytic lesions without sclerosis and a “salt and pepper” or “ground glass” appearance in the bones of the skull. Abdominal plain films revealed urolithiasis in several of our patients. CT is useful to identify the location, number and extent of the lesions,
FIGURE 1. Plain radiographic film (A) showing multiple lytic lesions in the pelvic ring. CT scan (B) showing boney defects in the acetabulum and pubic ramus with 2-dimensional CT reconstruction (C) and 3-dimensional CT reconstruction (D). The arrow (E) shows a space-occupying lesion in the left parathyroid gland area with the histologic result of parathyroid adenoma after cervical parathyroid CT. Copyright © 2015 by the Southern Society for Clinical Investigation.
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FIGURE 2. Parathyroid ECT (A) showing increased radioactive nuclide concentration in the parathyroid gland area of the lower left thyroid (arrow). Bone ECT (B) showing diffuse increased radioactive nuclide concentration in both the cortical bone of the proximal femur and the cancellous bone of the vertebrae. Photomicrograph showing the histopathology (C) of a parathyroid adenoma (maginification, 10 3 20).
and MRI can differentiate the tissue components of brown tumor based on the contrast of the signal intensity. The presence of hemosiderin deposition and fibrous stroma explains the low intensity on T2-weighted images.17 ECT is helpful to identify intact lesions and shows increased radioactive nuclide in the lytic lesions as a result of the osteoclast overactivity. Parathyroid radiography was performed to confirm the presence of parathyroid tumor in this study, and the authors stress that a single type of radiography examination, such as plain film,
TABLE 3. Information related to the operations Case Fracture Orthopedic surgery Misdiagnosis 1 2 3 4 5 6 7 8
0 0 0 0 0 1 1 1
0 0 0 0 1 1 1 1
0 0 0 0 1 1 0 0
easily leads to misdiagnosis. In this study, 2 cases (25%) were misdiagnosed mainly because local plain film radiography alone was performed, and patients were diagnosed as having a simple fracture and bone cyst. In cases of OFC, a combination of radiography methods is necessary to identify multiple lesions and avoid misdiagnosis. Some authors of this study hold the opinion that brown tumor presents in the late stages of PHPT without correct treatment and leads to increased bone turnover, deterioration of
Parathyroidectomy
Routine pathology
Follow-up (mo)
1 1 1 1 1 1 1 1
Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma Adenoma carcinoma
14 7 42 83 96 36 91 4
1, present; 0, absent.
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FIGURE 3. Plain radiographic film of the palm (A) showing diffuse subperiosteal bone resorption of the phalanges. Plain film (B) showing lytic lesions in both proximal femurs that were misdiagnosed as bone cyst and were followed with tumor curettage and allograft bone padding (C). Three years later, the lytic lesions had progressed on plain films (D) when the diagnosis of OFC was confirmed.
BMD and increased incidence of bone fracture.18–21 Most densitometry studies support that PTH is catabolic at cortical sites with anabolic effects at cancellous bone sites. Quantitative histomorphometric studies from iliac crest biopsies have revealed a 50% to 60% increase in bone turnover leading to increased bone resorption in PHPT patients.18,19,22 The results of plain radiography are unreliable. Only 3 case in this study, (37.5%), were defined as brown tumors on the basis of plain radiography and biochemical screening, and the others were misdiagnosed. Therefore, information from other sources must be taken into consideration. Bone fracture after minor trauma or spontaneous fracture is a dangerous signal alerting clinicians to underlying bone destruction. With increasing routine biochemical screening, hypercalcemia has been identified as an indicator of the presence of OFC. In this study, all 8 patients presented with hypercalcemia of varying levels. The clinical manifestations caused by hypercalcemia include kidney stones, nausea, peptic ulcers, appetite loss and weight loss, and “bones, stones, abdominal groans and psychic overtones.”23 As more sensitive biochemical screening is used, typical symptoms such as acute pancreatitis and peptic ulcer caused by hypercalcemia are uncommon.24 However, the extent of hypercalcemia may not reflect the severity of the clinical manifestations. Findings show, the serum calcium concentration in 1 patient who suffered severe peptic ulcer was only 3.14 mmol/L. However, the patient with the highest serum calcium (3.67 mmol/L) presented with only mild symptoms. Alkaline phosphatase, which is an index of bone turnover, was often increased in this study. Because of lack of examination service, the 25-hydroxyvitamin D data are absent in this study. However, some studies have proved that a low 25-hydroxyvitamin D level is accompanied by high PTH levels and both interact to increase disease activity in PHPT.25,26 This means that vitamin D deficiency can influence mineral metabolism to cause reduced cortical bone density or strength and vice versa.6,7,27,28 Therefore, vitamin D supplementation is useful in the treatment of OFC. Histologically, the bone disease in PHPT is described as an intensely vascular fibroblastic stroma background for cell populations consisting of rounded mononuclear cells mixed with a number of osteoclast-like multinucleated cells. Hemorrhage and hemosiderin deposition can sometimes also be seen. It is well Copyright © 2015 by the Southern Society for Clinical Investigation.
known that brown tumors exhibit no pathognomonic histologic changes, but the term is an effective way to exclude malignant tumors and metastasis, thus avoiding unnecessary surgery.29,30 Because of a lack of specificity in radiography and histology, making a diagnosis of OFC is not easy. Differentiating between a brown tumor and other tumors, such as giant cell tumor and giant cell reparative granuloma, may be difficult; however, the latter 2 rarely present with diffuse osteoporosis. The multiple lytic lesions seen radiographically are often mistreated as osteosarcoma, metastasis or multiple myeloma. Other differential diagnoses that should be considered include bone cyst, aneurysmal bone cystic, Paget’s disease and ossifying fibroma.31–34 In the authors experience, a correct OFC diagnosis depends on comprehensive clinical examinations. An in-depth medical history is very important including duration of malaise, bone pain or painful mass and details of any fracture. Biochemical screening is also important. Serum calcium and PTH should be examined at the same time because normal serum calcium occurs often in PHPT.30,33 A variety of bone imaging methods in combination with parathyroid radiography are also helpful to make the diagnosis. A bone biopsy before choosing surgery is necessary to exclude malignant bone tumors to avoid misdiagnosis. Parathyroidectomy has been shown to halt bone deterioration, improve BMD and reduce the risk of fracture in PHPT patients.10–12 The procedure also leads to regression of brown tumors.35,36 VanderWalde et al10 reported that patients who underwent parathyroidectomy compared with those who did not had a reduced risk of fracture regardless of age, or calcium or PTH level. Therefore, it is suggested that bone surgery is unnecessary for brown tumors.3,37 For patients with OFC who seek medical attention in orthopedic departments, the choice of treatment strategies is critical, especially when surgery is considered. The authors suggest that a precondition for surgery is a correct diagnosis. Then, surgical interventions can proceed in the following cases: for a large mass with or without severe bone pain, for a persistent aggressive mass, delayed treatment, bone fracture leading to functional disability or a high risk of disability, recurrence after surgery and considering patients’ wishes. Surgical treatments can relieve bone pain and improve quality of life, but parathyroidectomy must be performed before orthopedic surgery, or the orthopedic intervention is pointless
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(Figures 3B–D). In this study, 25% of the patients were misdiagnosed so cure of the primary disease was delayed, and recurrence occurred 1 year later in once case and 3 years later in another. The proportion of patients with OFC undergoing orthopedic surgeries is as high as 50%. Therefore, one must carefully consider the operative indications to avoid misdiagnosis and delayed treatment. Whether bone surgery can improve the regression rate requires large case-control studies to confirm. Not all patients are surgical candidates. The likelihood of parathyroidectomy decreases with increasing age, and the procedure is not recommended in older patients.38 Most studies favor medical therapy and recommend monitoring the serum calcium in the absence of clear and compelling empirical evidence.39,40 The most recent recommended guidelines are as follows: annual serum calcium, annual serum creatinine and bone density study every 1 to 2 years (3 sites).38 Oral calcium and calcitriol supplements are needed to control hypocalcemia. Bisphosphonates are frequently used, and this practice is supported by several clinical trials; however, serum and urinary calcium monitoring are suggested for longtime use.40 For emergency hypocalcemia symptoms, such as muscle spasm, calcium gluconate infusion can be useful. In conclusion, the presence of multisite osteolytic and boney giant cell lesions or fracture after minor trauma is an important clinical sign. A correct diagnosis of OFC alone will not correct the metabolic problems, but it can avoid unnecessary bone resection in most cases. However, if the surgical indications are appropriate for a patient, surgical intervention should be considered. REFERENCES 1. Guney E, Yigitbasi OG, Bayram F, et al. Brown tumor of the maxilla associated with primary hyperparathyroidism. Auris Nasus Larynx 2001;28:369–72. 2. Dogan A, Algun E, Kisli E, et al. Calcaneal brown tumor with primary hyperparathyroidism caused by parathyroid carcinoma: an atypical localization. J Foot Ankle Surg 2004;43:248–51.
12. Vestergaard P, Mollerup CL, Frokjaer VG, et al. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598–602. 13. Boudou P, Ibrahim F, Cormier C, et al. A very high incidence of low 25 hydroxy-vitamin D serum concentration in a French population of patients with primary hyperparathyroidism. J Endocrinol Invest 2006; 29:511–15. 14. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 2001;86:1212–21. 15. Guo CY, Thomas WE, al-Dehaimi AW, et al. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81: 3487–91. 16. Syed Z, Khan A. Skeletal effects of primary hyperparathyroidism. Endocr Pract 2000;6:385–8. 17. Rubin MR, Livolsi VA, Bandeira F, et al. Tc99m-sestamibi uptake in osteitis fibrosa cystica simulating metastatic bone disease. J Clin Endocrinol Metab 2001;86:5138–41. 18. Mosekilde L, Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperparathyroidism. Acta Med Scand 1978;204:97–102. 19. Charhon SA, Edouard CM, Arlot ME, et al. Effects of parathyroid hormone on remodeling of iliac trabecular bone packets in patients with primary hyperparathyroidism. Clin Orthop Relat Res 1982: 255–63. 20. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283–91. 21. Dempster DW, Cosman F, Parisien M, et al. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14:690–709. 22. Eriksen EF, Mosekilde L, Melsen F. Trabecular bone remodeling and balance in primary hyperparathyroidism. Bone 1986;7:213–21. 23. Maina AM, Kraus H. Successful treatment of osteitis fibrosa cystica from primary hyperparathyroidism. Case Rep Orthop 2012;2012:145760.
3. Scott SN, Graham SM, Sato Y, et al. Brown tumor of the palate in a patient with primary hyperparathyroidism. Ann Otol Rhinol Laryngol 1999;108:91–4.
24. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863–75.
4. Kearns AE, Thompson GB. Medical and surgical management of hyperparathyroidism. Mayo Clin Proc 2002;77:87–91.
25. Mishra SK, Agarwal G, Kar DK, et al. Unique clinical characteristics of primary hyperparathyroidism in India. Br J Surg 2001;88:708–14.
5. Marx SJ. Hyperparathyroid genes: sequences reveal answers and questions. Endocr Pract 2011;17(suppl 3):18–27.
26. Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005;257:6–17.
6. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: still evolving? J Bone Miner Res 1997;12:856–62. 7. Resendiz-Colosia JA, Rodriguez-Cuevas SA, Flores-Diaz R, et al. Evolution of maxillofacial brown tumors after parathyroidectomy in primary hyperparathyroidism. Head Neck 2008;30:1497–504. 8. Agarwal G, Mishra SK, Kar DK, et al. Recovery pattern of patients with osteitis fibrosa cystica in primary hyperparathyroidism after successful parathyroidectomy. Surgery 2002;132:1075–83; discussion 1083–1075. 9. Hoshi M, Takami M, Kajikawa M, et al. A case of multiple skeletal lesions of brown tumors, mimicking carcinoma metastases. Arch Orthop Trauma Surg 2008;128:149–54. 10. VanderWalde LH, Liu IL, Haigh PI. Effect of bone mineral density and parathyroidectomy on fracture risk in primary hyperparathyroidism. World J Surg 2009;33:406–11. 11. Rao DS, Wallace EA, Antonelli RF, et al. Forearm bone density in primary hyperparathyroidism: long-term follow-up with and without parathyroidectomy. Clin Endocrinol (oxf) 2003;58:348–54.
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27. Bilezikian JP, Meng X, Shi Y, et al. Primary hyperparathyroidism in women: a tale of two cities–New York and Beijing. Int J Fertil Womens Med 2000;45:158–65. 28. Stein EM, Dempster DW, Udesky J, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone 2011;48:557–61. 29. Al-Gahtany M, Cusimano M, Singer W, et al. Brown tumors of the skull base. Case report and review of the literature. J Neurosurg 2003; 98:417–20. 30. Emin AH, Suoglu Y, Demir D, et al. Normocalcemic hyperparathyroidism presented with mandibular brown tumor: report of a case. Auris Nasus Larynx 2004;31:299–304. 31. Lessa MM, Sakae FA, Tsuji RK, et al. Brown tumor of the facial bones: case report and literature review. Ear Nose Throat J 2005;84:432–4. 32. Martinez-Gavidia EM, Bagan JV, Milian-Masanet MA, et al. Highly aggressive brown tumour of the maxilla as first manifestation of primary hyperparathyroidism. Int J Oral Maxillofac Surg 2000;29:447–9.
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33. Suarez-Cunqueiro MM, Schoen R, Kersten A, et al. Brown tumor of the mandible as first manifestation of atypical parathyroid adenoma. J Oral Maxillofac Surg 2004;62:1024–8.
37. Daniels JS. Primary hyperparathyroidism presenting as a palatal brown tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98: 409–13.
34. Triantafillidou K, Zouloumis L, Karakinaris G, et al. Brown tumors of the jaws associated with primary or secondary hyperparathyroidism. A clinical study and review of the literature. Am J Otolaryngol 2006;27: 281–6.
38. Wu B, Haigh PI, Hwang R, et al. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2010;95:4324–30.
35. Endo I, Matsumoto T. Primary hyperparathyroidism [in Japanese]. Nihon Rinsho 2006;64:1718–23. 36. Arabi A, Khoury N, Zahed L, et al. Regression of skeletal manifestations of hyperparathyroidism with oral vitamin D. J Clin Endocrinol Metab 2006;91:2480–3.
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39. Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94:335–9. 40. Khan A, Bilezikian J. Primary hyperparathyroidism: pathophysiology and impact on bone. CMAJ 2000;163:184–7.
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