Joseph L. Shaker, MD
St. Luke’s Medical Center, Milwaukee, WI
Primary hyperparathyroidism (PHPT) is a common condition with prevalence in the general population of approximately 3 per 1000.1 The incidence peaks in midlife with the female to male ratio about 5:1 after age 55 years.1 The biochemical profile includes hypercalcemia with elevated or inappropriately normal levels of intact parathyroid hormone (the intact parathyroid hormone is typically suppressed in PTH-independent hypercalcemia) and normal to elevated urinary calcium.2 Incipient PHPT with normal calcium levels has recently been described.3 80-85% of patients with PHPT have a single parathyroid adenoma. 2 Multiple gland disease (more than one adenoma or hyperplasia) occurs about 15-20% of the time and parathyroid cancer is uncommon.2 With more common multichannel chemistry testing, the clinical presentation of PHPT has shifted from a symptomatic one with hypercalcemic symptoms, kidney stones and overt bone disease to a more asymptomatic condition.4 In the United States, survival does not appear to be adversely affected in patients with mild PHPT. 5 National Institutes of Health (NIH) guidelines for surgery in patients with asymptomatic PHPT from 2002 are outlined in Table 1.6 Surgery is recommended if any of the indications are present. Guidelines for monitoring patients who don’t have surgery are outlined in Table 2.6
Although it is well known that severe PHPT may be associated with osteitis fibrosis cystica and brown tumors, skeletal manifestations of more “typical” PHPT may not be the same. Furthermore, intermittent exposure to PTH has anabolic effects on bone. Relevant questions about the effects of PHPT on the skeleton include the following;
1. What is the bone histomorphometry in typical PHPT?
2. What is the relationship between bone mineral density (BMD) and fractures and PHPT?
3. Is the fracture incidence increased in PHPT?
4. What is the baseline BMD at diagnosis in PHPT and what happens to BMD over time in PHPT?
5. What is the effect of parathyroidectomy on BMD?
6. What is the effect of antiresorptive therapy on BMD in patients with PHPT?
7. What is the difference between parathyroidectomy and parathyroidectomy combined with antiresorptive therapy on BMD in patients with PHPT?
Bone histomorphometric data in patients with PHPT reveals decreased cortical width and increased cortical porosity.7 However, trabecular bone volume is maintained with preserved architecture and connectivity. 8 Bone turnover is increased in patients with PHPT.8 There is some data that suggests PHPT may be associated with increased diameter of bone which could compensate for decreased cortical thickness and increased cortical porosity with respect to bone strength.9,10
There is controversy about whether fractures are increased in patients with primary hyperparathyroidism. In a population-based study of 407 patients with PHPT by Khosla et al, 11 there did appear to be an increase in risk of fractures, particularly vertebral, forearm, rib, and pelvis. In a study of 674 patients with PHPT more severe than the typical patient in the U.S. (mean serum calcium of 11.8 mg/dl) who were compared to 2021 controls, the risk of fracture was increased up to 10 years before parathyroid surgery and declined after parathyroid surgery.12 Not all studies, however, found an increase in the risk of vertebral fractures in mild asymptomatic PHPT.13 It is likely that the differences in fracture risk among the studies can be attributed to the differences in severity of PHPT.
Densitometric studies of patients with PHPT have suggested that BMD is only slightly decreased at trabecular sites (e.g. lumbar spine) and more decreased at cortical sites such as the forearm. 7 However, there appears to be a subset of patients with vertebral osteopenia. 14 An important question is what happens to BMD in patients with primary hyperparathyroidism who are followed conservatively? Silverberg et al 15 followed patients with mild primary hyperparathyroidism for six years. They found lumbar spine, femoral neck and radius BMD to be stable. Grey et al 16 found evidence of decreasing total body BMD in patients being followed with mild PHPT. In a 10-year prospective study of patients with PHPT, BMD was on average stable. However, 11 of 52 (21%) asymptomatic patients had a decrease in BMD of greater than 10% over time. 17 It appears that BMD in mild PHPT is stable in most but not all patients. In a subset of patients, BMD decreases significantly. Other studies have suggested that interleukin-6, tumor necrosis factor-alpha, and interleukin-6 soluble receptor may be correlated with bone resorption and/or bone loss in PHPT.18,19,20
There is data on the effect of parathyroidectomy on BMD in PHPT. These patients tend to be more severely affected than those followed without surgery and often met criteria for surgery. These studies suggest that bone density improves significantly, particularly at the lumbar spine and proximal femur after successful parathyroid surgery.17,21,22,23,24 For example, Silverberg et al 21 found mean BMD increases at the lumbar spine of 8.2% at one year and 12.8% at four years and mean femoral neck BMD increases of 5.9% at one year and 12.7% at four years. The early increase in bone density may be related to filling the remodeling space (bone remodeling transient).25
It would be useful to know if antiresorptive agents have a beneficial effect on bone density in patients with PHPT who may be poor surgical candidates or who may decline surgery. Although an early study suggested serum calcium may decrease with estrogen therapy in postmenopausal women with PHPT,26 higher doses of estrogen than typically used in the clinical setting may be required to reduce the serum calcium significantly. Hormone therapy does, however, decrease markers of bone turnover and increase bone density in postmenopausal women with mild PHPT.27 Recently published data using raloxifene suggests a beneficial effect on bone density28 as well as decreased bone turnover and serum calcium 29 in postmenopausal women with PHPT. A number of studies have been published using alendronate in patients with PHPT. Alendronate does appear to decrease markers of bone resorption and increase bone density in these patients.30,31,32,33,34 Though a potential concern, patients with PHPT treated with alendronate do not appear to develop substantial persistent increases in parathyroid hormone. There is no data on whether antiresorptive drugs decrease fracture rate in PHPT and the authors of the summary of a NIH consensus meeting in 2002 did not believe there was enough data on the use of these drugs in PHPT to recommend their routine use.6
Cinacalcet, a calcimimetic agent that directly decreases parathyroid hormone secretion, has recently been approved for treatment of secondary hyperparathyroidism related to renal failure. Cinacalcet appears to decrease PTH and serum calcium levels in PHPT.35 However, bone density data are not yet available.
There is very little information about whether parathyroidectomy plus antiresorptive therapy will provide a greater increase in bone density than parathyroidectomy alone. One study of 13 postmenopausal women with parathyroidectomy and 8 postmenopausal women with parathyroidectomy plus estrogen therapy suggested there may be slightly greater increases in bone density at 12 months with estrogen therapy.36
Of note is that dietary calcium restriction is generally not recommended in PHPT. Current recommendations are to continue a prudent normal calcium intake of 1000-1200 mg daily and to maintain the 25-hydroxyvitamin D level greater than 20 ng/ml with replacement doses of vitamin D (e.g. 400-800 IU daily).6
In summary, PHPT is associated with decreased cortical width and increased cortical porosity with preservation of trabecular bone and architecture. Bone diameter may be increased. The bone density is somewhat decreased in PHPT especially at cortical sites. The bone density does appear to be stable over time in most but not all patients with mild PHPT. It is not known whether the relationship between bone density and fracture is quantitatively similar in PHPT to postmenopausal women. Although controversial, the fracture incidence may be increased in PHPT. Bone density does improve after parathyroidectomy and antiresorptive drugs appear to have skeletal protective effects in mild PHPT. There is very little data comparing the effect of parathyroidectomy with or without antiresorptive therapy on bone density after surgery and the effect of calcimimetic agents on bone density in PHPT is not known. Current guidelines for surgery in asymptomatic PHPT are in Table 1. Surgery should be considered in patients with a T-score less than -2.5 at the hip, spine or forearm.6 Yearly BMD measurement is recommended in patients who are being followed without surgery.6
Table 1 2002 Guidelines for Surgery in Asymptomatic PHPT (Adapted from reference 6)
|Serum Calcium (above upper nl)||Greater than 1.0 mg/dl|
|24 hour Urinary Calcium (mg)||Greater than 400|
|Creatinine Clearance||Reduced by 30%|
|BMD||T-score is less than -2.5 (hip, spine, forearm)|
|Age (years)||Less than 50|
Table 2 2002 Guidelines for Monitoring Patients with Asymptomatic PHPT (Adapted from reference 6)
|24 hour Urinary Calcium||Baseline|
|BMD||Annually – 3 sites (hip, spine, forearm)|
|Abdominal X-ray or ultrasound (for assessment of renal stones)||Baseline|
1. Melton LJ: The epidemiology of primary hyperparathyroidism in North America. J Bone Miner Res 2002;17:N12-N17.
2. Silverberg SJ, Bilezikian JP: Clinical presentation of primary hyperparathyroidism in the United States. In, Bilezikian JP, Marcus R, Levine MA eds. The Parathyroids, 2nd edition. San Diego: Academic Press, 2001:2:349-360.
3. Silverberg SJ, Bilezikian JP: “Incipient” primary hyperparathyroidism: A “forme fruste” of an old disease. J Clin Endocrinol Metab 2003;88:5348-52.
4. Bilezikian JP, Potts JT: Asymptomatic primary hyperparathyroidism: New issues and new questions — bridging the past with the future. J Bon Miner Res 2002:17:N57-N67.
5. Wermers RA, Khosla S, Atkinson EJ, et al: Survival after the diagnosis of hyperparathyroidism. Am J Med 1998;104:115-22.
6. Bilezikian JP, Potts JT, El-Hajj Fuleihan G, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidism: A perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353-61.
7. Silverberg SJ, Shane E, De La Cruz L, et al: Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989;4:283-91.
8. Parisien M, Cosman F, Mellish RWE, et al: Bone structure in postmenopausal hyperparathyroid, osteoporotic, and normal women. J Bone Miner Res 1995;10:1393-99.
9. Adami S, Braga V, Squaranti R, et al: Bone measurements in asymptomatic primary hyperparathyroidism. Bone 1998:22;565-70.
10. Khairalla TS, Reddy V, Phillips C, et al: Effect of mild hyperparathyroidism on bone density, geometry and strength. ISCD meeting, 2004 (Abstract 89).
11. Khosla S, Melton LJ, Wermers RA, et al: Primary hyperparathyroidism and the risk of fracture: A population-based study. J Bone Miner Res 1999;14:1700-1707.
12. Vestergaard P, Mollerup C, Gedso Frokjaer V, et al: Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000;321:598-602.
13. Wilson RJ, Rao DS, Ellis B, et al: Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med 1988;109:959-62.
14. Silverberg SJ, Locker FG, Bilezikian JP: Vertebral osteopenia: A new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007-12.
15. Silverberg SJ, Gartenberg F, Jacobs TP, et al: Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:723-8.
16. Grey AB, Stapleton JP, Evans MC, et al: Accelerated bone loss in post-menopausal women with mild primary hyperparathyroidism. Clin Endocrinol 1996;44:697-702.
17. Silverberg SJ, Shane E, Jacobs TP, et al: A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl Med 1999;341:1249-55.
18. Grey A, Mitnick MA, Shapses S, et al: Circulating levels of interleukin-6 and tumor necrosis factor- α are elevated in primary hyperparathyroidism and correlate with markers of bone resorption — a clinical research center study. J Clin Endocrinol Metab 1996;81:3450-4.
19. Grey A, Mitnick MA, Masiukiewicz U, et al: A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology 1999;140:4683-90.
20. Nakchbandi IA, Mitnick MA, Lang R, et al: Circulating levels of interleukin-6 soluble receptor predict rates of bone loss in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2002;87:4946-51.
21. Silverberg SH, Gartenberg F, Jacobs TP, et al: Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:729-34.
22. Christiansen P, Steiniche T, Brixen K, et al: Primary hyperparathyroidism: short-term changes in bone remodeling and bone mineral density following parathyroidectomy. Bone 1999;25:237-44.
23. Abe Y, Ejima E, Fujiyama K, et al: Parathyroidectomy for primary hyperparathyroidism induces positive uncoupling and increases bone mineral density in cancellous bones. Clin Endocrinol 2000;52:203-9.
24. Nomura R, Sugimoto T, Tsukamoto T, et al: Marked and sustained increase in bone mineral density in patients with primary hyperparathyroidism: a six-year longitudinal study with or without parathyroidectomy in a Japanese population. Clin Endocrinol 2004;60:335-42.
25. Heaney RP: The basis for the post-parathyroidectomy increase in bone mass. J Bone Miner Res 2002;17:N154-N157.
26. Marcus R, Madvig P, Crim M, et al: Conjugated estrogens in the treatment of postmenopausal women with primary hyperparathyroidism. Ann Intern Med 1984;100:633-40.
27. Orr-Walker BJ, Evans MC, Clearwater JM, et al: Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism. Arch Intern Med 2000;160:2161-6.
28. Zanchetta JR, Bogado CE: Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism. J Bone Miner Res 2001;16:189-190.
29. Rubin MR, Lee KH, McMahon DJ, et al: Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:1174-8.
30. Rossini M, Gatti D, Isaia G, et al: Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001;16:113-9.
31. Hassani S, Braunstein GD, Seibel MJ, et al: Alendronate therapy of primary hyperparathyroidism. The Endocrinologist 2001;11:459-64.
32. Parker CR, Blackwell PJ, Fairbairn KJ, et al: Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study. J Clin Endocrinol Metab 2002;87:4482-9.
33. Chow CC, Chan WB, Li JKY, et al: Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:581-7.
34. Khan AA, Bilezikian JP, Kung AWC, et al: A double blind placebo controlled trial of alendronate in primary hyperparathyroidism (abstract). J Bone Miner Res 2003 (supplement 2):18;F421.
35. Shoback DM, Bilezikian JP, Turner SA, et al: The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644-9.
36. El-Hajj Fuleihan G, Moore F, LeBoff MS, et al: Longitudinal changes in bone density in hyperparathyroidism. J Clin Densitom 1999;2:153-62.
Last modified: December 17, 2012