The presentation of hyperparathyroidism changed over the last decades which gave rise to more variable presentations than before. Hyperparathyroidism has a catabolic effect on the skeleton whether the disease is symptomatic or asymptomatic or normocalcemic. It is now understood that the effect of parathyroid hormone (PTH) on the bone is mediated by complex interaction between different bone cells and cells of the immune system especially T lymphocytes. Protecting the skeletal system against bone loss and pathological fractures is among the important treatment goals of hyperparathyroidism. To achieve this goal, more complex laboratory tests to monitor the bone turnover and imaging techniques and modalities as high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) are employed. These imaging techniques showed the affection of microarchitecture of the cortical and the trabecular bone. For the time being, surgery and alendronate treatment are believed to reverse the catabolic effect of hyperparathyroidism on the bone. Vitamin D supplementation in case of vitamin D deficiency may also has a protective effect on the skeleton.
- osteitis fibrosa cystica (OFC)
- brown tumor
- parathyroid hormone
- bone metabolism
Over the last hundred years, the effect of parathyroid hormone (PTH) on bone metabolism was extensively discussed. PTH acts on the bone cells through several mediators, and its action involves a variety of cells. It is now understood that parathyroid hormone has both catabolic and anabolic effects on bone metabolism . Mandl in Austria was the first to prove that the enlarged parathyroid was responsible for the skeletal manifestations of hyperparathyroidism after the first successful removal of parathyroid adenoma . The clinical picture of the disease also changed dramatically over the years from a disease of “stones, bones, abdominal groans, thrones and psychiatric overtone” to a disease which can be only detected by elevated calcium and the PTH level on laboratory tests or even the elevated PTH level with no hypercalcemia [2, 3]. This change in clinical presentation was accompanied by the introduction of newer lab tests to assess bone turnover and newer imaging techniques to assess the bone quality . The treatment modalities also evolved, allowing more individualized approach for treating each patient .
2. Action of parathyroid hormone on the bone in hyperparathyroidism
The main function of PTH is to maintain calcium levels within the normal range thorough its action on the bone, kidneys, and intestine. It also decreases serum phosphorous through inhibiting renal reabsorption [5, 6]. PTH can produce catabolic or anabolic effect on bone metabolism depending on the level of the hormone, periodicity, and duration of exposure [6, 7]. Primary hyperparathyroidism (PHPT), continuous PTH infusion (cPTH), and intermittent PTH treatment (iPTH) increase bone turnover in trabecular and cortical bone and elevate the markers for bone resorption and formation [2, 8, 9, 10]. PHPT and cPTH enhance cortical bone loss by increasing osteoclastic activity but produce cancellous bone that is relatively preserved or modestly increased [2, 9, 11]. iPTH treatment stimulates trabecular bone formation by osteoblast stimulation and can cause small cortical bone loss [12, 13]. The pattern of bone loss in PHPT is different from the pattern of bone loss in osteoporosis. In osteoporosis, the trabecular bone loss predominates, while in PHPT the cortical bone loss predominates .
2.1. Action of parathyroid hormone on bone cells
Normally, bone structural integrity is maintained by the process or remodeling where the bone is removed by osteoclasts and new bone is synthesized by osteoblasts . The osteoclasts and osteoblasts are arranged in a structure called the basic multicellular unit (BMU). A BMU consists of osteoclasts in front with osteoblasts, some blood vessels, and connective tissue behind [16, 17]. Osteoclasts are formed by fusion of mononuclear precursors, while osteoblasts originate from undifferentiated mesenchymal cells [16, 18]. Parathyroid hormone produces its effects by binding to its receptor PPR (also known as PTH-1R). While osteoblasts, osteocytes, and lymphocytes, mesenchymal stromal cells express PPR, osteoclasts respond indirectly to PTH through various mediators and cytokines produced by cells which carry PPR [6, 19, 20, 21, 22, 23]. It is now believed that osteocytes are the primary cellular target of PTH in the bone. Osteocytes are the main cells that express PPR in the musculoskeletal system . Saini et al. designed a study where they generated mice with PPR deletion in osteocytes. These mice showed significant increase in bone mineral density (BMD), reduced osteoblast activity, and decreased skeletal response to anabolic or catabolic PTH regimen . Other studies also supported the fact that osteocytes rather than osteoblasts are the main source of the receptor activator of nuclear factor kappa-B ligand (RANKL) in the process of osteoclastogenesis [25, 26]. Where mice lacking RANKL in osteocytes had less bone loss compared to control mice when they are exposed to dietary calcium deficiency for 30 days causing secondary hyperparathyroidism. There was less RANKL expression and less osteoclast number in the group of mice lacking RANKL . Another study was designed with a co-culture of osteoclast precursors and osteocytes. The study showed that RANKL is provided through dendritic processes of osteocytes to osteoclast precursor and that soluble RANKL had less contribution to osteoclastogenesis . In humans, the RANKL/osteoprotegerin (OPG) ratio is higher in patients with PHPT than controls. This ratio is decreased with parathyroidectomy (PTx) or medical treatment by alendronate . Another study on patients with PHPT showed that RANKL correlated with bone resorption markers in these patients and suggested that it can be used to determine patients of PHPT with greater risk of bone loss . Another study was conducted on patients with PHPT where transiliac bone biopsy was done before PTx and 12 months after surgery and mRNA for RANKL and OPG were measured. The study showed that the mRNA ratio of RANKL/OPG decreased significantly after surgery .
PTH increases RANKL/OPG ratio with continuous exposure to high dose which produces catabolic effect as in hyperparathyroidism. This results in increased bone turnover, osteopenia, and bone loss in hyperparathyroidism. In addition, several extraskeletal manifestations of hyperparathyroidism are due to increased bone catabolism and hypercalcemia as nephrolithiasis, renal failure, peptic ulcer, and mental changes . On the other hand, intermittent low-dose exposure to PTH has an anabolic effect through the SOST/sclerostin pathway .
The OPG-RANK-RANKL pathway is the mechanism by which hyperparathyroidism induces bone catabolism. PTH regulates the production of RANKL and its soluble decoy receptor OPG by osteoblasts and osteocytes [29, 30, 31]. RANKL binds to the receptor activator of nuclear factor kappa-B (RANK) on the osteoclast precursor stimulating their differentiation to osteoclasts and on the surface of the osteoclasts increasing their bone-resorbing activity. OPG inhibits the action of RANKL by binding to RANKL, thus preventing its access to the receptor RANK. In this way, the process of bone resorption is controlled by the balance between the concentration of RANKL and OPG [32, 33, 34, 35, 36]. In rats, continuous infusion of human PTH increased RANKL and RANKL mRNA expression and decreased OPG and OPG mRNA . In vitro studies also showed that PTH activates of cAMP/PKA–CREB pathway increase the Tnfsf11 gene encoding RANKL, whereas a PTH inhibits the mRNA encoding for OPG expression through a PKA-CREB-AP-1 pathway [38, 39, 40].
2.2. Effect of parathyroid hormone on cells of the bone marrow and cells of the immune system
Cells of bone marrow also play a role in the effect of PTH on bone metabolism. Lymphocytes are believed to play a role on bone metabolism. T lymphocytes express PPR . T cells express RANKL and CD40L on their surface that binds with RANK and CD40 in osteoclast precursors and osteoclasts to stimulate them [13, 41, 42]. Th17 cells form a subset of T lymphocytes that contribute to bone resorption. TH17 cells secrete IL-17, RANKL, TNF-α, IL-1, and IL-6, along with low levels of IFN-γ which contribute to osteoclastogenesis [43, 44, 45, 46]. IL-17 stimulates the secretion of RANKL by osteoblasts and osteocytes and upregulates RANK [46, 47]. This is consistent with a human study that showed statistically significant elevation of IL-17 in postmenopausal women who had osteoporosis when compared with postmenopausal women who had osteopenia . It is also noted that cPTH stimulates the production of TGF-β, IL-6, and TNF-α by bone cells and stromal cells [7, 48, 49]. TGF-β and IL-6 direct the differentiation of naive CD4+ cells into TH17 cells [50, 51, 52]. TNF-α plays also an important role as a mediator of PTH catabolic action. PTH stimulates T cells to produce TNF-α. In mice lacking T-cell TNF-α, PTH failed to produce bone resorption but did not affect bone formation. Thus, in these mice there was no cortical bone loss, and there was increased trabecular bone formation . TNF-α stimulates osteoclast formation and activity by multiple mechanisms. TNF-α increases the production of RANKL by osteoblasts and osteocytes. It also increases the expression of CD40 by stromal cells and osteoblasts increasing their responsiveness to CD40L expressed by T cells. Activation of CD40 on stromal cells and osteoblasts decreases the OPG secretion, thus increasing the RANKL/OPG ratio .
Bone marrow macrophages also play a role in the action of PTH on the bone. Macrophages express PPR. Depletion of the precursors of macrophages decreases the anabolic effect of iPTH . The monocyte chemoattractant protein-1 (MCP-1) which is a chemotactic factor for monocyte and macrophages is a mediator for PHT-induced bone resorption . MCP-1 was proven to attract pre-osteoclast in in vitro studies, thus increasing bone resorption . It was found that the expression for MCP-1 increased by cPTH and iPTH in rat osteoblastic cells. With cPTH the MCP-1 expression was sustained, while with the anabolic protocol, the expression of MCP-1 was transient yet more pronounced. This suggests that the transient increase of bone resorption may be necessary before the anabolic effect of PTH on the bone [53, 54]. In human studies, MCP-1 levels correlate with PTH levels in patients with PHPT. After PTx, the levels of MCP-1 decreased significantly starting from 15 minutes following parathyroid adenoma removal .
3. Skeletal abnormalities in symptomatic hyperparathyroidism
Hyperparathyroidism was first described in 1891 by von Recklinghausen. Despite of the fact that primary hyperparathyroidism was classically described as disease of “stones, bones, abdominal groans, thrones, and psychiatric overtone,” the presentation of the disease changed dramatically over the past decades. Nowadays, the classical presentation with osteitis fibrosa cystica and pathological fractures is rarely seen in developed countries. Currently, larger numbers of patients are being identified with neuropsychiatric or cardiac manifestation and laboratory studies in the USA and Europe [2, 56]. In developing countries, the symptomatic form of PHPT was prevalent for a long time, but some countries as Brazil and China are having a shift toward the asymptomatic disease. However, other countries as India, Iran, Saudi Arabia, and Thailand still have high prevalence of the symptomatic form of the disease with pronounced skeletal manifestations [56, 57, 58].
3.2. Clinical manifestations
The signs and symptoms of severe bone disease include bone pain and pathologic fractures. Skeletal muscles are also affected by hyperparathyroidism where the patients have proximal muscle weakness and hyperreflexia [2, 59].
One of the features of skeletal involvement in hyperparathyroidism is hungry bone syndrome. It is characterized by hypocalcemia and hypophosphatemia following PTx. It is thought to be due to withdrawal of osteoclast stimulation by high levels of PTH. This condition is treated by high doses of calcium and vitamin D [60, 61].
Plain X-rays can show the classical findings of osteitis fibrosa cystica. This is characterized by marked thinning of the cortex (demineralization). Salt and pepper appearance for skull X-rays is also seen. Bone resorption of distal third of the clavicle is also seen. Hand X-rays show subperiosteal bone erosions in the distal phalanges and the lateral aspects of middle phalanges. Lytic lesions can also be seen in the pelvis and long bones with pathological fractures. Lytic lesions are referred to as brown tumors; these are a mixture of hemosiderin (hence, the brown color on pathological examination), woven bone, fibrous tissue, and osteoclasts. However, the lesions are nonneoplastic .
188.8.131.52. Bone mineral density
Bone mineral density can be measured by dual energy X-ray absorptiometry (DEXA) scan in all patients where measurements should be taken for lumbar spine, hip regions (total hip and femoral neck), and distal 1/3 of the radius. It is important to measure the bone mineral density in distal radius as it is a cortical site, and hyperparathyroidism is known to have catabolic effect on cortical bone [2, 56].
184.108.40.206. High-resolution peripheral quantitative computed tomography (HR-pQCT)
This is a noninvasive technique that allows assessment of the cortical and trabecular bone quality in PHPT . HR-pQCT measures volumetric bone density, bone geometry, skeletal microarchitecture, and bone strength in the cortical and trabecular compartments. HR-pQCT showed that microarchitectural deterioration in both cortical and cancellous sites has decreased volumetric densities, more widely spaced, and heterogeneously distributed trabeculae and thinner cortices [62, 63, 64].
220.127.116.11. Trabecular bone score (TBS)
TBS is obtained from DEXA scan by applying special software. It is a textural analysis that provides an indirect index of trabecular microarchitecture. It can differentiate between DEXA scans showing similar bone densities. A high TBS is associated with a dense trabecular network and greater bone strength, and a low TBS indicates poor microarchitecture and poor strength [65, 66, 67].
Histomorphometry of transiliac biopsy will show reduced width of the cortex with increased porosity, while the trabecular bone is preserved .
3.3.3. Laboratory tests
In severe PHPT, serum calcium and parathormone are elevated. There are special markers for bone elevation as osteocalcin, type I procollagen peptide, and alkaline phosphatase. Alkaline phosphatase is much above the normal in all cases of hyperparathyroidism with increased bone turnover. Markers of bone resorption are also typically elevated PHPT. These include deoxypyridinoline, N-telopeptide, and C-telopeptide. These markers are products of breakdown of type 1 collagen . Renal functions and urinary calcium should be evaluated. 25OH vitamin D levels should be as lower as the levels of 25OH vitamin D correlate with higher bone turnover and lower BMD, and both improve with repletion of 25OH vitamin D [68, 69].
4. Skeletal abnormalities in asymptomatic primary hyperparathyroidism
In 1970s, the wide availability of measurement of serum calcium changed the clinical presentation of hyperparathyroidism giving rise to the entity of asymptomatic primary hyperparathyroidism . These are patients with hypercalcemia and elevated PTH but who are discovered accidentally while doing laboratory studies . These patients have no X-ray finding of symptomatic hyperparathyroidism previously described . These patients show decreased bone mass in cortical sites when measured by DEXA scan. Thus, DEXA scan shows reduction of bone mineral density at distal 1/3 of forearm (which is composed primarily of cortical bone), while bone density of lumbar spine (which is formed mainly of trabecular bone) is preserved. However, bone scan may remain stable for years in patients with asymptomatic hyperparathyroidism. Rubin et al. noted that the BMD of the lumbar spine remained stable for 15 years while it started to fall in cortical sites before 10 years [70, 71]. Micro-CT and histomorphometric studies show reduction of cortical bone with preservation of cancellous bone in PHPT [70, 71]. However, clinical studies showed that patients with hyperparathyroidism have higher risk of fractures both at cortical and cancellous sites [72, 73]. HR-pQCT helped to resolve this controversy. HR-pQCT showed that microarchitectural deterioration in both cortical and cancellous sites has decreased volumetric densities, more widely spaced, and heterogeneously distributed trabeculae and thinner cortices [62, 63, 64]. These studies also highlighted that weight bearing is a factor that can prevent the microarchitectural deterioration where they showed that the radius is more negatively affected than the tibias [63, 64]. Stein et al. performed individual trabecula segmentation that gave an insight into the trabecular microstructure. They found that the number of plate-like trabeculae is reduced relative to the rod-like trabeculae (decrease P-R ratio); there is reduced connectivity and less axially aligned trabecular network . Another imaging modality which can show skeletal affection in asymptomatic cases is the trabecular bone score (TBS). Romagnoli et al. showed that TBS was significantly lower in patients with PHPT compared to controls. Among patients with PHPT, TBS was significantly lower in patients with vertebral fractures when compared to patients without vertebral fractures . Eller-Vainicher et al. showed that TBS was associated with vertebral fractures regardless of age, gender, BMD, and BMI .
4.2. Natural history of bone disease in asymptomatic hyperparathyroidism
Age and female genders are associated with higher fracture risk in PHPT . Currently, it is still unclear whether fracture risk assessment tools as FRAX can help to predict risk of fractures in patients with PHPT or not . Concerning changes in BMD over time, Rao et al. monitored 80 patients with asymptomatic PHPT for a mean of 46 month. They did not observe deterioration of biochemical markers nor BMD measurements . Silverberg et al. followed up 121 patients with PHPT of whom 101 were asymptomatic for up to 10 years. Twenty-five percent of patients showed disease progression. They also noted that patients younger than 50 years old had more likelihood of disease progression . Rao et al. conducted randomized controlled trial on patients with PHPT and concluded that BMD at the hip and spine improves after PTx . Rubin et al. studied 116 patients with PHPT of whom 99 were asymptomatic, PTX improved the biochemical markers and BMD, and without surgery PHPT progressed in one third of the cases . Eller-Vainicher et al. studied 92 patients with PHPT and 98 controls for 24 months. DEXA scan and TBS in patients treated surgically and conservatively. In the surgical group, BMD and TBS increased significantly although it remained lower than controls. In the conservative group, BMD showed a decrease which was not statistically significant, and TBS showed a decrease which was not statistically significant; except in three patients who had vertebral fractures, the TBS showed a statistically significant decrease . Hansen et al. measured BMD and HR-pQCT in women with PHPT before and 1 year after PTx. BMD improved after PTx, and HR-pQCT showed improvement of the cortical and trabecular parameters of the radius and tibia .
5. Skeletal abnormalities in normocalcemic primary hyperparathyroidism
This is a cohort of patients which includes patients with normal total and ionized calcium but elevated PTH in the absence of causes of secondary hyperparathyroidism. This may be due to target organ resistance of the bone and kidney, or these patients are in early stages of the disease [78, 79]. Lowe et al. described a cohort of patients in whom 57% had osteoporosis, 11% had fragility fractures, and 14% had renal stones . Amaral et al. compared normocalcemic to hypercalcemic PHPT patients. They found that 15% of normocalcemic patients had previous fractures compared to 10.8% of normocalcemic patients and the incidence of renal stones was 18.2 in normocalcemic vs. 18.9% of hypercalcemic patients . Charopoulos et al. used peripheral quantitative CT to compare the effect of normocalcemic PHPT to the effect of hypercalcemic PHPT on volumetric BMD and bone geometry. They noted the catabolic effect on both groups although it is more severe in the hypercalcemic group. In the normocalcemic group, cortical properties were adversely affected, while the trabecular properties were preserved .
5.2. Natural history of bone disease in asymptomatic hyperparathyroidism
The natural history of bone loss in normocalcemic hyperparathyroidism is not fully defined. Lowe et al. showed decrease in BMD by at least 5% in 43% of the patients . Koumakis et al. measured BMD before and 12 months after PTx for patients with normocalcemic and hypercalcemic PHPT. Both groups showed statistically significant improvement of BMD at the postoperative measurement .
6.1. Effect of surgery on the skeletal manifestations of hyperparathyroidism
Skeletal affection is among the indications of surgery in hyperparathyroidism. Even in asymptomatic cases, surgery is suggested for perimenopausal or postmenopausal women and men 50 years or older who have a T-score of −2.5 or less for any skeletal site. In premenopausal women and men under 50 years old, T-score of less than −2.5 is the cutoff for surgery. The presence of fragility fractures is also among the surgical indication [2, 4, 81].
Surgery improves the bone turnover marker and PTH level. Within the first year following surgery, the BMD improves [70, 71, 82, 83]. This is due to uncoupling of bone resorption where the osteoclast stimulation by PTH stops, while bone formation continues . Rubin et al. showed that the gain in BMD was sustainable up to 15 years following surgery at cortical and cancellous sites despite of expected age-related losses in BMD. The increases in BMD were recorded in the study at years 1, 5, and 10 and showed that the lumbar spine increased to 9, 6, and 12%; the femoral neck 1, 7, and 10%; and the distal radius 4, 8, and 7% . Christiansen et al. studied the BMD and bone turnover markers for the first 6 months after surgery. They reported that the bone turnover markers were normalized and increased bone density in regions rich in cancellous bone but not cortical bone . Similarly, Silverberg et al. noted improvement of BMD in lumbar spine and femoral neck but not the radius . This may be explained by the fact that remodeling in cortical sites is slower than in trabecular bone. Thus, it takes a longer time for changes to be more pronounced . Surgery also decreases the risk of fractures in hyperparathyroidism [72, 85, 86]. Vestergaard et al. demonstrated that the risk of fractures started to increase 10 years prior to surgery and reached its maximum 5–6 years following surgery. This risk falls back to normal after surgery . Rudser et al. compared patients on dialysis who receive PTx to patients on dialysis without PTx. Fracture risks were lower among hemodialysis patients who underwent PTx compared to the dialysis patients who did not undergo PTx .
6.2. Effect of pharmacological treatment on skeletal manifestations of hyperparathyroidism
Bisphosphonates (BP) are used in treatment of hyperparathyroidism as they act by inhibiting osteoclastic activity which is the cause of hypercalcemia and bone loss . Several studies assessed the use of alendronate in hyperparathyroidism. Studies reported a reduction in the level of bone turnover markers and an increase in BMD. The increase in BMD was more for the trabecular than the cortical sites [87, 88, 89, 90, 91, 92]. Although alendronate can lower the serum calcium initially, serum calcium tends to rise over 6 months, and the level of PTH may increase more than the pretreatment level [2, 90, 91, 92, 93]. Pamidronate in several studies showed lowering of the serum calcium. However, due to limited time frame, no changes in BMD nor complications were reported [94, 95, 96, 97, 98, 99, 100]. Clodronate use was associated with lowering of the serum calcium [101, 102, 103]. Several studies using clodronate reported lowering of urinary hydroxyproline and hence decreased bone turnover [101, 102, 103]. The use of risedronate in treatment of hyperparathyroidism was assessed in few studies [104, 105]. Tournis et al. reported that surgery is superior to risedronate as it improved the BMD and trabecular mineralization. Risedronate treatment in their study did not result in significant change in volumetric BMD or peripheral quantitative computed tomography . A small number of studies reported the use of several BPs. Lee et al. reported the can prevent hungry bone syndrome among a very small number of patients . Two other studies reported increase in BMD in the lumbar spine and hip [85, 106].
In conclusion, alendronate is the most studied BP in hyperparathyroidism. It decreases bone turnover and increased BMD. The effect of alendronate on serum calcium appears to be short lived.
This is a calcimimetic agent which increases the sensitivity of calcium-sensing receptors of the parathyroid gland to calcium, thus decreasing PTH secretion . The effect of cinacalcet on bone turnover markers and BMD appears to be controversial. Several studies measured bone turnover markers with either decrease in the markers , no change [109, 110], or increase in the level of the markers [111, 112]. Similarly, the reported effects on BMD were an increase in BMD , a decrease , and no change [108, 111, 112]. Faggiano et al. compared cinacalcet monotherapy with cinacalcet with alendronate. The patients who received the combined therapy had better improvement of BMD in lumbar spine and hip compared to the monotherapy group. There was no significant difference between biochemical changes in both groups . Moe et al. studied the effect of cinacalcet in reducing the fracture risk in patients receiving hemodialysis. There was no significant effect of cinacalcet on fracture reduction in the intention-to-treat analysis. However, a lag-sensoring analysis which took into consideration the crossover effect showed significant reduction of fracture risk in patients who received cinacalcet .
6.2.3. Vitamin D and calcium
Dietary calcium deficiency can induce elevation of PTH levels. Low vitamin D levels are associated with increased bone turnover, deteriorated hip geometry, and lower BMD [68, 84, 115]. Patients with low calcium intake and PHPT who received calcium supplementation had lower levels of PTH and improved BMD of femoral neck . For patients with vitamin D deficiency, vitamin D repletion may decrease PTH levels and improved bone mineral density [116, 117, 118]. However, vitamin D supplementation may slightly increase serum calcium levels and urinary calcium excretion; thus, monitoring of calcium levels is valuable [81, 119, 120].
6.2.4. Other treatments of hyperparathyroidism which affect bone metabolism
Estrogen was found to improve BMD in women with hyperparathyroidism. The BMD of the lumbar spine and femoral neck increases, and bone turnover markers decrease with estrogen administration which has no or minimal effect on serum calcium [121, 122]. Raloxifene was also associated with improved BMD in PHPT [123, 124]. However, there is no data on the effect of estrogen or raloxifene on reducing the risk of fracture .
Denosumab is a monoclonal antibody against RANKL that inhibits the binding of RANKL to RANK . A study was conducted on patients with secondary hyperparathyroidism on dialysis in whom denosumab was administered. The BMD improved in the femoral neck and lumbar spine. However, a transient increase in PTH levels occurred in the patients.
Despite of the fact that many patients with hyperparathyroidism do not show symptoms of skeletal affection, clinicians always need to keep an eye on the catabolic effect of hyperparathyroidism on the skeletal system. Better understanding of the mechanism of action of PTH of bone showed that many cells and mediators can influence the RANK/RANKL/OPG system, namely, T lymphocytes. Newer imaging modalities as TBS and HR-pQCT can be useful for detecting subtle bony changes. While parathyroidectomy is proven to reverse the skeletal effects of hyperparathyroidism, many patients may not be indicated for surgery, yet they should receive medical treatment that will protect them from the catabolic effect on the bone. Alendronate was extensively studied and showed to decrease bone turnover and increase BMD. Vitamin D supplementation for patients with vitamin D deficiency has a protective effect on the bone. Denosumab also has a protective effect, but clinical data about its use for patients with hyperparathyroidism is still limited.
I would like to thank Assistant Professor Stephen Mendelson (Assistant Professor in Department of Orthopedic Surgery in University of Pittsburgh, USA) and Professor Sherif Khaled (Professor of Orthopedic Surgery in Faculty of Medicine, Cairo University, Egypt) for their endless support to accomplish this work.
Conflict of interest
The author has no conflict of interests to declare.
Malluche HH, Koszewski N, Monier-Faugere MC, Williams JP, Mawad H. Influence of the parathyroid glands on bone metabolism. European Journal of Clinical Investigation. 2006; 36(Suppl 2):23-33
Elizabeth A, Streeten MAL. Hyperparathyroidism, primary. In: Martini L, editor. Encyclopedia of Endocrine Disease. Amsterdam: Elsevier; 2004. p. 558-566
Habib Z, Camacho P. Primary hyperparathyroidism: An update. Current Opinion in Endocrinology, Diabetes, and Obesity. 2010; 17(6):554-560
Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet (London, England). 2017
Civitelli R, Ziambaras K. Calcium and phosphate homeostasis: Concerted interplay of new regulators. Journal of Endocrinological Investigation. 2011; 34(7 Suppl):3-7
Silva BC, Bilezikian JP. Parathyroid hormone: Anabolic and catabolic actions on the skeleton. Current Opinion in Pharmacology. 2015; 22:41-50
Pacifici R. T cells, osteoblasts, and osteocytes: Interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Annals of the New York Academy of Sciences. 2016; 1364(1):11-24
Iida-Klein A, Lu SS, Kapadia R, Burkhart M, Moreno A, Dempster DW, et al. Short-term continuous infusion of human parathyroid hormone 1-34 fragment is catabolic with decreased trabecular connectivity density accompanied by hypercalcemia in C57BL/J6 mice. The Journal of Endocrinology. 2005; 186(3):549-557
Zhou H, Shen V, Dempster DW, Lindsay R. Continuous parathyroid hormone and estrogen administration increases vertebral cancellous bone volume and cortical width in the estrogen-deficient rat. Journal of Bone and Mineral Research. 2001; 16(7):1300-1307
Dempster DW, Parisien M, Silverberg SJ, Liang XG, Schnitzer M, Shen V, et al. On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 1999; 84(5):1562-1566
Hock JM, Gera I. Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone. Journal of Bone and Mineral Research. 1992; 7(1):65-72
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. The New England Journal of Medicine. 2001; 344(19):1434-1441
Nakchbandi IA, Lang R, Kinder B, Insogna KL. The role of the receptor activator of nuclear factor-κB ligand/osteoprotegerin cytokine system in primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2008; 93(3):967-973
Koumakis E, Souberbielle J-C, Sarfati E, Meunier M, Maury E, Gallimard E, et al. Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2013; 98(8):3213-3220
Parfitt AM. Skeletal heterogeneity and the purposes of bone remodeling: Implications for the understanding of osteoporosis. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. 2nd ed. Florida: Academic Press; 2001. p. 433-477
Manolagas SC. Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews. 2000; 21(2):115-137
Parfitt AM. Osteonal and hemi-osteonal remodeling: The spatial and temporal framework for signal traffic in adult human bone. Journal of Cellular Biochemistry. 1994; 55(3):273-286
Owen M. The origin of bone cells in the postnatal organism. Arthritis and Rheumatism. 1980; 23(10):1073-1080
Cho SW, Soki FN, Koh AJ, Eber MR, Entezami P, Park SI, et al. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111(4):1545-1550
Lanske B, Amling M, Neff L, Guiducci J, Baron R, Kronenberg HM. Ablation of the PTHrP gene or the PTH/PTHrP receptor gene leads to distinct abnormalities in bone development. The Journal of Clinical Investigation. 1999; 104(4):399-407
Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. The Journal of Clinical Investigation. 2001; 107(3):277-286
Powell WF, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, et al. Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. The Journal of Endocrinology. 2011; 209(1):21-32
Terauchi M, Li J-Y, Bedi B, Baek K-H, Tawfeek H, Galley S, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metabolism. 2009; 10(3):229-240
Saini V, Marengi DA, Barry KJ, Fulzele KS, Heiden E, Liu X, et al. Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. The Journal of Biological Chemistry. 2013; 288(28):20122-20134
Xiong J, Piemontese M, Thostenson JD, Weinstein RS, Manolagas SC, O’Brien CA. Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency. Bone. 2014; 66:146-154
Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nature Medicine. 2011; 17(10):1231-1234
Honma M, Ikebuchi Y, Kariya Y, Hayashi M, Hayashi N, Aoki S, et al. RANKL subcellular trafficking and regulatory mechanisms in osteocytes. Journal of Bone and Mineral Research. 2013; 28(9):1936-1949
Szymczak J, Bohdanowicz-Pawlak A. Osteoprotegerin, RANKL, and bone turnover in primary hyperparathyroidism: The effect of parathyroidectomy and treatment with alendronate. Hormone and Metabolic Research. 2013; 45(10):759-764
O’Brien CA, Nakashima T, Takayanagi H. Osteocyte control of osteoclastogenesis. Bone. 2013; 54(2):258-263
Kanzawa M, Sugimoto T, Kanatani M, Chihara K. Involvement of osteoprotegerin/osteoclastogenesis inhibitory factor in the stimulation of osteoclast formation by parathyroid hormone in mouse bone cells. European Journal of Endocrinology. 2000; 142(6):661-664
Lee S-K, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: Correlation with osteoclast-like cell formation 1. Endocrinology. 1999; 140(8):3552-3561
Khosla S. Minireview: The OPG/RANKL/RANK system. Endocrinology. 2001; 142(12):5050-5055
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proceedings of the National Academy of Sciences of the United States of America. 1998; 95(7):3597-3602
Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. The Journal of Experimental Medicine. 1998; 188(5):997-1001
Simonet WS, Lacey D, Dunstan CR, Kelley MCMS, Chang M, Lüthy R, et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-319
Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocrine Reviews. 2008; 29(2):155-192
Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, et al. Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology. 2001; 142(9):4047-4054
Fu Q, Jilka RL, Manolagas SC, O’Brien CA. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. The Journal of Biological Chemistry. 2002; 277(50):48868-48875
Lee S-K, Lorenzo JA. Regulation of receptor activator of nuclear factor-kappa B ligand and osteoprotegerin mRNA expression by parathyroid hormone is predominantly mediated by the protein kinase a pathway in murine bone marrow cultures. Bone. 2002; 31(1):252-259
Kondo H, Guo J, Bringhurst FR. Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. Journal of Bone and Mineral Research. 2002; 17(9):1667-1679
Pacifici R. Osteoimmunology and its implications for transplantation. American Journal of Transplantation. 2013; 13(9):2245-2254
Di Rosa F. T-lymphocyte interaction with stromal, bone and hematopoietic cells in the bone marrow. Immunology and Cell Biology. 2009; 87(1):20-29
Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. Journal of Immunology. 1998; 160(7):3513-3521
Waisman A. T helper cell populations: As flexible as the skin? European Journal of Immunology. 2011; 41(9):2539-2543
Komatsu N, Takayanagi H. Autoimmune arthritis: The interface between the immune system and joints. Advances in Immunology. 2012:45-71
Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. The Journal of Experimental Medicine. 2006; 203(12):2673-2682
Adamopoulos IE, Chao C-C, Geissler R, Laface D, Blumenschein W, Iwakura Y, et al. Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors. Arthritis Research & Therapy. 2010; 12(1):R29
Koh AJ, Novince CM, Li X, Wang T, Taichman RS, McCauley LK. An irradiation-altered bone marrow microenvironment impacts anabolic actions of PTH. Endocrinology. 2011; 152(12):4525-4536
Löwik CW, van der Pluijm G, Bloys H, Hoekman K, Bijvoet OL, Aarden LA, et al. Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: A possible role of interleukin-6 in osteoclastogenesis. Biochemical and Biophysical Research Communications. 1989; 162(3):1546-1552
Basu R, Hatton RD, Weaver CT. The Th17 family: Flexibility follows function. Immunological Reviews. 2013; 252(1):89-103
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-238
Martinez GJ, Nurieva RI, Yang XO, Dong C. Regulation and function of proinflammatory TH17 cells. Annals of the New York Academy of Sciences. 2008; 1143(1):188-211
Li X, Qin L, Bergenstock M, Bevelock LM, Novack DV, Partridge NC. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. The Journal of Biological Chemistry. 2007; 282(45):33098-33106
Tamasi JA, Vasilov A, Shimizu E, Benton N, Johnson J, Bitel CL, et al. Monocyte chemoattractant protein-1 is a mediator of the anabolic action of parathyroid hormone on bone. Journal of Bone and Mineral Research. 2013; 28(9):1975-1986
Patel H, Trooskin S, Shapses S, Sun W, Wang X. Serum monocyte chemokine protein-1 levels before and after parathyroidectomy in patients with primary hyperparathyroidism. Endocrine Practice. 2014; 20(11):1165-1169
Silverberg SJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: Proceedings of the Fourth International Workshop. The Journal of Clinical Endocrinology and Metabolism. 2014; 99(10):3580-3594
Zhao L, Liu J-M, He X-Y, Zhao H-Y, Sun L-H, Tao B, et al. The changing clinical patterns of primary hyperparathyroidism in Chinese patients: Data from 2000 to 2010 in a single clinical center. The Journal of Clinical Endocrinology and Metabolism. 2013; 98(2):721-728
Bandeira F, Cusano NE, Silva BC, Cassibba S, Almeida CB, Machado VCC, et al. Bone disease in primary hyperparathyroidism. Arquivos Brasileiros de Endocrinologia e Metabologia. 2014; 58(5):553-561
Bandeira F, Griz L, Caldas G, Bandeira C, Freese E. From mild to severe primary hyperparathyroidism: The Brazilian experience. Arquivos Brasileiros de Endocrinologia e Metabologia. 2006; 50(4):657-663
Brasier AR, Nussbaum SR. Hungry bone syndrome: Clinical and biochemical predictors of its occurrence after parathyroid surgery. The American Journal of Medicine. 1988; 84(4):654-660
Komaba H, Kakuta T, Fukagawa M. Management of secondary hyperparathyroidism: How and why? Clinical and Experimental Nephrology. 2017; 21(S1):37-45
Vu TDT, Wang XF, Wang Q, Cusano NE, Irani D, Silva BC, et al. New insights into the effects of primary hyperparathyroidism on the cortical and trabecular compartments of bone. Bone. 2013; 55(1):57-63
Hansen S, Beck Jensen J-E, Rasmussen L, Hauge EM, Brixen K. Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT. Journal of Bone and Mineral Research. 2010; 25(9):1941-1947
Stein EM, Silva BC, Boutroy S, Zhou B, Wang J, Udesky J, et al. Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. Journal of Bone and Mineral Research. 2013; 28(5):1029-1040
Roux JP, Wegrzyn J, Boutroy S, Bouxsein ML, Hans D, Chapurlat R. The predictive value of trabecular bone score (TBS) on whole lumbar vertebrae mechanics: An ex vivo study. Osteoporosis International. 2013; 24(9):2455-2460
Hans D, Barthe N, Boutroy S, Pothuaud L, Winzenrieth R, Krieg M-A. Correlations between trabecular bone score, measured using anteroposterior dual-energy X-ray absorptiometry acquisition, and 3-dimensional parameters of bone microarchitecture: An experimental study on human cadaver vertebrae. Journal of Clinical Densitometry. 2011; 14(3):302-312
Silva BC, Leslie WD, Resch H, Lamy O, Lesnyak O, Binkley N, et al. Trabecular bone score: A noninvasive analytical method based upon the DXA image. Journal of Bone and Mineral Research. 2014; 29(3):518-530
Moosgaard B, Christensen SE, Vestergaard P, Heickendorff L, Christiansen P, Mosekilde L. Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism. Clinical Endocrinology. 2008; 68(5):707-715
Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IR. Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. The Journal of Clinical Endocrinology and Metabolism. 2005; 90(4):2122-2126
Rubin MR, Bilezikian JP, McMahon DJ, Jacobs T, Shane E, Siris E, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. The Journal of Clinical Endocrinology and Metabolism. 2008; 93(9):3462-3470
Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. The New England Journal of Medicine. 1999; 341(17):1249-1255
Vestergaard P, Mollerup CL, Frøkjaer VG, Christiansen P, Blichert-Toft M, Mosekilde L. Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ. 2000; 321(7261):598-602
Khosla S, Melton LJ, Wermers RA, Crowson CS, O’Fallon WM, Riggs BL. Primary hyperparathyroidism and the risk of fracture: A population-based study. Journal of Bone and Mineral Research. 1999; 14(10):1700-1707
Romagnoli E, Cipriani C, Nofroni I, Castro C, Angelozzi M, Scarpiello A, et al. “Trabecular bone score” (TBS): An indirect measure of bone micro-architecture in postmenopausal patients with primary hyperparathyroidism. Bone. 2013; 53(1):154-159
Eller-Vainicher C, Filopanti M, Palmieri S, Ulivieri FM, Morelli V, Zhukouskaya VV, et al. Bone quality, as measured by trabecular bone score, in patients with primary hyperparathyroidism. European Journal of Endocrinology. 2013; 169(2):155-162
Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2004; 89(11):5415-5422
Hansen S, Hauge EM, Rasmussen L, Jensen J-EB, Brixen K. Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: A one-year prospective controlled study using high-resolution peripheral quantitative computed tomography. Journal of Bone and Mineral Research. 2012; 27(5):1150-1158
Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: A “forme fruste” of an old disease. The Journal of Clinical Endocrinology and Metabolism. 2003; 88(11):5348-5352
Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism: Evidence for a generalized target-tissue resistance to parathyroid hormone. The Journal of Clinical Endocrinology and Metabolism. 2003; 88(10):4641-4648
Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism: Further characterization of a new clinical phenotype. The Journal of Clinical Endocrinology and Metabolism. 2007; 92(8):3001-3005
Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the Fourth International Workshop. The Journal of Clinical Endocrinology and Metabolism. 2014; 99(10):3561-3569
Bollerslev J, Jansson S, Mollerup CL, Nordenström J, Lundgren E, Tørring O, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: A prospective, randomized trial. The Journal of Clinical Endocrinology and Metabolism. 2007; 92(5):1687-1692
Christiansen P, Steiniche T, Brixen K, Hessov I, Melsen F, Heickendorff L, et al. Primary hyperparathyroidism: Short-term changes in bone remodeling and bone mineral density following parathyroidectomy. Bone. 1999; 25(2):237-244
Lee JH, Kim JH, Hong AR, Kim SW, Shin CS. Skeletal effects of vitamin D deficiency among patients with primary hyperparathyroidism. Osteoporosis International. 2017; 28(5):1667-1674
Yeh MW, Zhou H, Adams AL, Ituarte PHG, Li N, Liu I-LA, et al. The relationship of parathyroidectomy and bisphosphonates with fracture risk in primary hyperparathyroidism: An observational study. Annals of Internal Medicine. 2016; 164(11):715-723
Rudser KD, de Boer IH, Dooley A, Young B, Kestenbaum B. Fracture risk after parathyroidectomy among chronic hemodialysis patients. Journal of the American Society of Nephrology. 2007; 18(8):2401-2407
Khan AA, Bilezikian JP, Kung AWC, Ahmed MM, Dubois SJ, Ho AYY, et al. Alendronate in primary hyperparathyroidism: A double-blind, randomized, placebo-controlled trial. The Journal of Clinical Endocrinology and Metabolism. 2004; 89(7):3319-3325
Khan A, Bilezikian J, Kung A, Dubois S, Standish T, Syed Z. Alendronate therapy in men with primary hyperparathyroidism. Endocrine Practice. 2009; 15(7):705-713
Cesareo R, Di Stasio E, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporosis International. 2015; 26(4):1295-1302
Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ. Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: A 2-year study. The Journal of Clinical Endocrinology and Metabolism. 2002; 87(10):4482-4489
Akbaba G, Isik S, Ates Tutuncu Y, Ozuguz U, Berker D, Guler S. Comparison of alendronate and raloxifene for the management of primary hyperparathyroidism. Journal of Endocrinological Investigation. 2013; 36(11):1076-1082
Chow CC, Chan WB, Li JKY, Chan NN, Chan MHM, Ko GTC, et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2003; 88(2):581-587
Adami S, Mian M, Bertoldo F, Rossini M, Jayawerra P, O’Riordan JL, et al. Regulation of calcium-parathyroid hormone feedback in primary hyperparathyroidism: Effects of bisphosphonate treatment. Clinical Endocrinology. 1990; 33(3):391-397
Phitayakorn R, McHenry CR. Hyperparathyroid crisis: Use of bisphosphonates as a bridge to parathyroidectomy. Journal of the American College of Surgeons. 2008; 206(6):1106-1115
Jansson S, Morgan E. Biochemical effects from treatment with bisphosphonate and surgery in patients with primary hyperparathyroidism. World Journal of Surgery. 2004; 28(12):1293-1297
Ammann P, Herter-Clavel C, Lubrano A, Rizzoli R. A single bisphosphonate infusion is associated with improved functional capacity in elderly subjects with primary hyperparathyroidism. Aging Clinical and Experimental Research. 2003; 15(6):500-504
Schmidli RS, Wilson I, Espiner EA, Richards AM, Donald RA. Aminopropylidine diphosphonate (APD) in mild primary hyperparathyroidism: Effect on clinical status. Clinical Endocrinology. 1990; 32(3):293-300
Ishimura E, Miki T, Koyama H, Harada K, Nakatsuka K, Inaba M, et al. Effect of aminohydroxypropylidene diphosphonate on the bone metabolism of patients with parathyroid adenoma. Hormone and Metabolic Research. 1993; 25(9):493-497
Jansson S, Tisell LE, Lindstedt G, Lundberg PA. Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism. Surgery. 1991; 110(3):480-486
van Breukelen FJ, Bijvoet OL, Frijlink WB, Sleeboom HP, Mulder H, van Oosterom AT. Efficacy of amino-hydroxypropylidene bisphosphonate in hypercalcemia: Observations on regulation of serum calcium. Calcified Tissue International. 1982; 34(4):321-327
Hamdy NA, Gray RE, McCloskey E, Galloway J, Rattenbury JM, Brown CB, et al. Clodronate in the medical management of hyperparathyroidism. Bone. 1987; 8(Suppl 1):S69-S77
Douglas DL, Kanis JA, Paterson AD, Beard DJ, Cameron EC, Watson ME, et al. Drug treatment of primary hyperparathyroidism: Use of clodronate disodium. British Medical Journal (Clinical Research Ed.). 1983; 286(6365):587-590
Shane E, Baquiran DC, Bilezikian JP. Effects of dichloromethylene diphosphonate on serum and urinary calcium in primary hyperparathyroidism. Annals of Internal Medicine. 1981; 95(1):23-27
Tournis S, Fakidari E, Dontas I, Liakou C, Antoniou J, Galanos A, et al. Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism. Journal of Bone and Mineral Metabolism. 2014; 32(2):151-158
Reasner CA, Stone MD, Hosking DJ, Ballah A, Mundy GR. Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate. The Journal of Clinical Endocrinology and Metabolism. 1993; 77(4):1067-1071
Segula D, Nikolova T, Marks E, Ranganath L, Mishra V. Long term outcome of bisphosphonate therapy in patients with primary hyperparathyroidism. International Journal of Clinical Medicine. 2014; 5(14):829-835
Nemeth EF, Heaton WH, Miller M, Fox J, Balandrin MF, Van Wagenen BC, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. The Journal of Pharmacology and Experimental Therapeutics. 2004; 308(2):627-635
Faggiano A, Di Somma C, Ramundo V, Severino R, Vuolo L, Coppola A, et al. Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism. Endocrine. 2011; 39(3):283-287
Cetani F, Saponaro F, Banti C, Cianferotti L, Vignali E, Chiavistelli S, et al. Cinacalcet efficacy in patients with moderately severe primary hyperparathyroidism according to the European medicine agency prescription labeling. Journal of Endocrinological Investigation. 2012; 35(7):655-660
Giusti F, Cianferotti L, Gronchi G, Cioppi F, Masi L, Faggiano A, et al. Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to multiple endocrine neoplasia syndrome type 1 (MEN1). Endocrine. 2016; 52(3):495-506
Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2005; 90(1):135-141
Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheng S, et al. Cinacalcet treatment of primary hyperparathyroidism: Biochemical and bone densitometric outcomes in a five-year study. The Journal of Clinical Endocrinology and Metabolism. 2009; 94(12):4860-4867
Keutgen XM, Buitrago D, Filicori F, Kundel A, Elemento O, Fahey TJ, et al. Calcimimetics versus parathyroidectomy for treatment of primary hyperparathyroidism: Retrospective chart analysis of a prospective database. Annals of Surgery. 2012; 255(5):981-985
Norman J, Lopez J, Politz D. Cinacalcet (Sensipar) provides no measurable clinical benefits for patients with primary hyperparathyroidism and may accelerate bone loss with prolonged use. Annals of Surgical Oncology. 2012; 19(5):1466-1471
Stein EM, Dempster DW, Udesky J, Zhou H, Bilezikian JP, Shane E, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone. 2011; 48(3):557-561
Jorde R, Szumlas K, Haug E, Sundsfjord J. The effects of calcium supplementation to patients with primary hyperparathyroidism and a low calcium intake. European Journal of Nutrition. 2002; 41(6):258-263
Rolighed L, Bollerslev J, Mosekilde L. Vitamin D treatment in primary hyperparathyroidism. Current Drug Safety. 2011; 6(2):100-107
Walker MD, Cong E, Lee JA, Kepley A, Zhang C, McMahon DJ, et al. Vitamin D in primary hyperparathyroidism: Effects on clinical, biochemical, and densitometric presentation. The Journal of Clinical Endocrinology and Metabolism. 2015; 100(9):3443-3451
Bollerslev J, Marcocci C, Sosa M, Nordenström J, Bouillon R, Mosekilde L. Current evidence for recommendation of surgery, medical treatment and vitamin D repletion in mild primary hyperparathyroidism. European Journal of Endocrinology. 2011; 165(6):851-864
Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L, et al. Primary hyperparathyroidism: Review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporosis International. 2017; 28(1):1-19
Grey AB, Stapleton JP, Evans MC, Tatnell MA, Reid IR. Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Annals of Internal Medicine. 1996; 125(5):360-368
Selby PL, Peacock M. Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. The New England Journal of Medicine. 1986; 314(23):1481-1485
Zanchetta JR, Bogado CE. Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism. Journal of Bone and Mineral Research. 2001; 16(1):189-190
Rubin MR, Lee KH, McMahon DJ, Silverberg SJ. Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. The Journal of Clinical Endocrinology and Metabolism. 2003; 88(3):1174-1178
Schieferdecker A, Voigt M, Riecken K, Braig F, Schinke T, Loges S, et al. Denosumab mimics the natural decoy receptor osteoprotegerin by interacting with its major binding site on RANKL. Oncotarget. 2014; 5(16):6647-6653