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Bone mineral density in patients with lithium-associated hyperparathyroidism

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Örebro University

Institution of medical science Bachelor thesis, 15 ECTS June 2019

Bone mineral density in patients with

lithium-associated hyperparathyroidism

Author:

Basma Albaldawi Supervisor:

Adrian Meehan, MD, Dept. of Geriatrics Örebro, Sweden

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Abstract

Background

:

Lithium is the most effective long-term treatment for bipolar disease. It has, however, been associated with hypercalcemia and hyperparathyroidism. The aim of the study is to research how lithium associated hyperparathyroidism (LHPT) affects bone mineral density. Method: A sub-analysis was performed on an ongoing randomized prospective study evaluating the operation results from parathyroidectomy versus watchful waiting in 22 patients with LHPT. The patients were followed-up for 2 years and their blood samples, bone mineral density (BMD) and FRAX assessment were analysed. The data from LHPT patients was also compared to a separate group of patients with primary hyperparathyroidism (PHPT) corresponding in age. Results: In comparing LHPT patients with PHPT apparent differences in the biochemical profile were detected, including elevated values of ionized Ca in PHPT (p=0.001), lower excretion of 24h urinary calcium in LHPT (p=0.003) and significantly higher values of PTH excretion in PHPT. LHPT showed tendencies to having better BMD (p=0.176). At 2-year follow-up of 8 LHPT patients, biochemical values improved, suggesting cure, including lower risks of skeletal fractures.

Discussion: The biochemical features in LHPT are distinctive from PHPT. However, each case is unique, and the biochemical variety is similar to PHPT. Confounding factors include age, sex, renal function and stability of the bipolar condition.

Conclusions

:

The present study illustrates that LHPT differs biochemically from PHPT. In comparison to PHPT, LHPT patients tend to have reduced BMD and the present study could not confirm the previous postulation that lithium could be protective of the skeleton. In conclusion, cases of LHPT should be assessed individually, since the clinical course is diverse. In patients risking fracture, parathyroidectomy should be considered.

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Abbreviations

BD- Bipolar Disorder

LHPT- Lithium-associated hyperparathyroidism IMPase- Inositol monophosphatase

GSK-3- Glycogen synthase kinase 3 cAMP- Cyclic adenosine monophosphate

FHH- Benign familial hypocalciuric hypercalcemia PHPT- Primary hyperparathyroidism

PTH- Parathyroid hormone CaSR- Calcium sensing receptor iCa- Ionized serum calcium BMD- Bone mineral density ALP- Alkaline phosphatase tCa- Total calcium

uCaE- 24h urinary calcium excretion DEXA- Dual-energy x-ray absorptiometry FRAX- Fracture risk assessment tool

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Table of Contents

Background ... 5

Aim of the study ... 8

Method ... 8

Compliance with ethical standards ... 9

Results ... 10

Discussion ... 12

Primary hyperparathyroidism and lithium-associated hyperparathyroidism ... 13

Lithium-associated hyperparathyroidism, calcium and bone mineral density ... 14

Lithium treatment and the kidney ... 14

Bipolar disease and risk of fracture ... 15

Limitations ... 15 Conclusion ... 16 Acknowledgement ... 16 References ... 16 Appendix 1. ... 20 Appendix 2 ... 21 Appendix 3 ... 22

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Background

Lithium was introduced in 1949 and has since become the most effective long-term therapy for Bipolar Disorder (BD) [1]. In addition, it is the only anti-suicidal medication to reduce the suicide risk beyond 50% [1]. Treatment with lithium has, however, been associated with hypercalcemia, with the condition lithium-associated hyperparathyroidism (LHPT) being first described by Garfinkel et al. in 1973 [2]. Since then, approximately 400 cases of LHPT have been described in the English literature. The mechanisms by which lithium functions are not fully understood, but it is believed to act through inhibition of inositol monophosphatase (IMPase), glycogen synthase kinase 3 (GSK-3), Protein Kinase C and cyclic adenosine

monophosphate (cAMP) formation [2–4]. The significance of lithium therapy on the human bone structure is still vague and not entirely elucidated [5].

Hyperparathyroidism is one of many conditions, including malignancies, sarcoidosis and benign familial hypocalciuric hypercalcemia (FHH), that leads to the development of hypercalcemia [6]. Hyperparathyroidism can lead to reduced bone mass and development of osteopenia, and in time to osteoporosis, thus greatly, amplifying the risk of fracture [7]. Osteoporotic fractures impair quality of life, in addition to increasing the risk of morbidity, disability and mortality of many patients [8]. Each year about 70 000 osteoporotic fractures occur in Sweden, costing about 3,5 billion SEK [9]. Therefore, it is of significance to investigate if lithium therapy contributes to fractures.

Primary hyperparathyroidism (PHPT) is characterized by an elevation of parathyroid hormone (PTH) production [10], usually caused by a single adenoma in 85% of cases. Occasionally the underlying lesion is hyperplasia in all four parathyroid glands, and rarely parathyroid carcinoma [11]. PHPT is the third most common endocrine disorder, with a prevalence of approximately 1.0%, with the highest incidence rate occurring between the ages of 50-60 years [12]. It occurs four times more frequently in women, primarily postmenopausal [7].

PHPT can be biochemically described by the inappropriate elevation of PTH in relation to disturbances in calcium homeostasis, with changes ranging from normal to abnormally high. Diagnosis is based on the relationship between s-PTH and ionized calcium, given that kidney

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6 function is normal [6]. In that plasma calcium is more commonly assessed, PHPT is nowadays diagnosed incidentally, hence it is the most frequent cause of clinically asymptomatic

hypercalcemia. Symptomatic PHPT, however, causes a constellation of symptoms correlated to the elevated PTH and calcium levels, including nephrolithiasis, osteoporosis and fracture [7]. The development of nephrolithiasis is caused by the increased urinary excretion of calcium (due to the greater intestinal calcium absorption and the higher net bone turnover) exceeding the increased calcium tubular reabsorption [5]

Approximately 15 000 patients are treated with lithium in Sweden [13]. Lithium treatment is associated with a number of conditions, including weight gain, cardiovascular disease, diabetes and end stage renal failure. The estimated risk of developing LHPT is 10%, according to McKnight et al. [14]. The prevalence of LHPT is an estimated 26%, although it could vary 4.3-80%, depending on the size of the study [2]. The female to male ratio is 4:1, which corresponds with the gender ratio in PHPT [15].

In both in vitro and in vivo experiments, lithium ions antagonize calcium sensing receptors (CaSR) in the parathyroid cells, resulting in a right-shift, or a "set-point error” in the relationship between calcium and PTH excretion [5]. The set-point describes a homeostatic state in which a certain level of ionized calcium ions (iCa) suppresses the half-maximal release of PTH [16]. The right-shift reduces the calcium sensitivity in parathyroid cells, resulting in reduced negative feedback and enhanced PTH secretion [5] (Figure 1). It is speculated that the mechanism by which lithium antagonizes CaSR is through the inhibition of IMPase [17].

Figure 1.

Figure 1. PTH release in relation to serum ionized calcium in control (whole line) and lithium treated (dashed line) patients. The set-point is right shifted, indicating that more iCa is required to suppress PTH release [16].

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7 Hyperparathyroidism can be a result of the development of parathyroid adenoma and/ or

hyperplasia [3]. The inhibition of GSK-3 by lithium contributes to abnormal Wnt/β-catenin signalling, promoting the progression of adenomas and hyperplasia [6,18,19]. Indeed, according to Mallette et al. [20], parathyroid volume increases in patients after long-term treatment with lithium.

Theoretically, the volume increase would be equal in all parathyroid glands [2]. Numerous studies suggest that patients with LHPT are more likely to develop multiglandular disease compared with PHPT [2, 20], although the prevalence varies considerably between different studies (18.8-83%) [22]. Nordenström et al. [23] reported that parathyroid adenoma was more common in patients treated with lithium in the short-term, while parathyroid cell hyperplasia was more common in patients treated long-term with lithium.

Stancer and Forbath [24] analysed 19 patients treated with lithium for 10 to 20 years and discovered that the metabolic features in patients with LHPT differed from primary

hyperparathyroidism. The different metabolic features are illustrated in Table 1. The serum ionized calcium concentration is mildly increased, and the PTH concentration is abnormally elevated relative to the level of calcium. Nevertheless, the PTH levels are not always above the reference range. Lithium treated patients displayed low urinary calcium excretion, no

nephrolithiasis, normal plasma phosphate and normal to low urinary cAMP excretion [8,9]. LHPT patients have commonly been found to present biochemically with hypocalciuric

hypercalcemia. This may be due to lithium’s effects on CaSR, which are ubiquitous, and are also localized in the thick ascending limb of the renal tubule. Their inhibition results in a decreased urinary excretion of calcium. Indeed, the hypocalciuria in FHH arises through inhibition of CaSR [22]. Another theory is that lithium inhibits the formation of renal cAMP, which blunts PTH action on renal ion transport. This is consistent with the low cAMP excretion perceived in LHPT patients [3].

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8 Table 1. Illustrates the general differences in biochemical features in PHPT and LHPT

[3,10,11,24,25].

PTH iCa uCaE Phosphate Renal cAMP BMD

PHPT ↑→ ↑ ↑ ↓ ↑ ↓

LHPT ↑→ ↑→ ↓→ → ↓→ ↑→

It is of importance to assess correctly lithium-treated patients, determine their risk in developing side-effects of lithium treatment and to establish and optimize healthcare options which are tailored for the individual. Since LHPT possibly affects a fifth of all patients, identifying the patients at risk of fracture or other complications of the disease could prevent future discomfort. A better understanding of LHPT can be gained by assessing the condition by comparing it to PHPT, which all individuals can develop.

Aim of the study

The aim of the present study is to research and evaluate the biochemical characteristics and bone mineral density of LHPT in comparison to PHPT.

Method

A sub-analysis was performed on an ongoing randomized prospective study evaluating the operation results from parathyroidectomy in lithium treated patients with LHPT. Twenty-two patients were selected according to inclusion and exclusion criteria (see attachment 1). The inclusion criteria qualify patients between the ages of 20-75 years, undergoing lithium therapy and having a confirmed LHPT defined as iCa>1.34 or total Ca >2.50 and PTH > 65, independent of (OH)D-Vitamin.

Patients meeting the criteria were randomized to either parathyroidectomy or conservative management and are followed up for 2 years through numerous testing methods, including blood tests and questionnaires. The blood samples measured iCa, total calcium (tCa), 24h urinary calcium excretion (uCaE), PTH, phosphate, Vitamin D, s-creatinine and estimated glomerular filtration rate (eGFR), which is a measure for renal function. The references for the tests were

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9 collected from the sampling instructions by the laboratory medical clinic in Örebro University Hospital. The questionnaires (see attachment 2, 3) inquired information about patients’ length, weight, duration of lithium treatment, earlier fracture, renal stones (nephrolithiasis) and known conditions like low BMD (osteopenia) and osteoporosis.

The follow-up also included measurement of patients’ BMD by Dual-energy x-ray

absorptiometry (DEXA) and fracture risk assessment tool (FRAX) at the start and end of the 2-year period. The DEXA scan evaluates the BMD through a T-score, defined as the standard deviations between patients’ BMD and the reference population. According to WHO, T-score between -1 and -2.5 is determined osteopenia and ≤2.5 is osteoporosis. DEXA imaging is the gold standard method for identifying osteoporosis [26]. FRAX algorithms can predict 10-year probabilities of osteoporotic fracture, based on patient variables such as age, BMI, gender, smoking, history of fracture, glucocorticoid use. It can integrate the risks with femoral neck BMD (measured by DEXA) [27].

The results consist of 3 parts: I) The comparison of biochemical features and BMD in LHPT with PHPT groups. Reference data from 22 patients with PHPT, corresponding in age with the LHPT group, was collected from the medical department and used to compare values between LHPT/PHPT. Six patients from PHPT group were missing DEXA measurements. Descriptive statistics along with percentage, median value and range was used to evaluate the data. The p-value was calculated using the Two-tailed Students´ unpaired T-test in Excel version 1904. The p-value for statistical significance was set at 0.05. II) The evaluation of patients’ demographics and conditions, using only descriptive statistics. III) The biochemical and bone density

comparison of LHPT patients at the start and end of the study. Only 8 patients have completed the 2-year period. The p-value was calculated using Students´ paired T-test in Excel.

Compliance with ethical standards

Studying the underlying mechanism of lithium induced HPT and its consequences on the bone density is sophisticated and requires clinical trial. There are no laboratory animals equivalent to human bipolar population. Participating in the study means that the patients journal and personal information are examined, meaning a risk of privacy breaching. Although, I personally will not partake or contain any personal data that could be connected to the patients. Furthermore,

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10 patients are exposed to radiation (low dose) and venepuncture in order to take the necessary tests, though these can be considered to standard optimal treatment. The parathyroidectomy carries a <1% risk of complication. The study was ethically authorized, and the patients gave their verbal and written consent to participate. Its significance lies in determining whether lithium causes an increased or a decreased BMD and the effective following management of the condition.

Results

The result show that 82% of LHPT patients had iCa above the reference range at inclusion in the study, though higher values occurred earlier giving rise to suspected parathyroid pathology), see table 2. Also, 64% had tCa above the reference range. The hypercalcemia (iCa) and

hypercalciuria (uCaE) in PHPT patients was more prominent. A total of 6 PHPT patients had hypercalciuria and only one had hypocalciuria. In comparison, eight LHPT patients had

hypocalciuria, and the rest had low calcium urinary excretion. The noticeable difference in PTH is that in the PHPT group, PTH could reach very high levels. Five PHPT patients had PTH levels above 100.

Seven patients in the LHPT group displayed moderately decreased renal function (stage 3 renal failure). Among these seven patients were the highest FRAX assessment (median value 15%) and lowest T-scores (median value -2.5). Only 3 patients in the PHPT group showed decreased renal function.

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Table 2. The biochemical features and T-score in patients with LHPT and PHPT, presented with median value and range.

*The phosphate reference is influenced by diet, age and sex. The reference chosen was for women, as most of the patients are women. ** The collected data from PHPT patients did not include FRAX assessment.

The demographics investigated in the present study were age, sex, lithium treatment, earlier fracture, osteopenia and nephrolithiasis (see table 3). Even though osteopenia was more common in patients with LHPT, the fracture rate was approximately identical.

Table 3. Describing the demographics of patients in LHPT and PHPT groups.

After the 2-year follow-up, the most noticeable changes in the LHPT group, (described in table 4) were of tCa (p=0.017), PTH (p= 0.100), FRAX and T-score.

Biochemical features LHPT, n=22 PHPT, n=22 p -value

iCa (1.2-1.35 mmol/L) 1.4 (1.3-1.5) 1.5 (1.4-1.6) 0.001 tCa (2.18-2.6 mmol/L) 2.6 (2.5-2.9) 2.7 (2.2-4.3) 0.071 uCaE (2.5-8.0 mmol/24h) 2.6 (0.7-7.4) 7.1 (1.6-13) 0.003 PTH (1.6-6.9 pmol/L) 8.9 (4.9-19.1) 11.5 (7-800) 0.084 Vit-D (>75 nmol/L) 68 64 Phosphate (0.8-1.5 mmol/L)* 1 (0.7-1.7) 0.9 (0.7-1.2) 0.043 FRAX** 8.6 /

T-score -1.9 (normal-(-16)) -0.5 (normal-(-2.8)) 0.176 eGFR (>90 mL/min/1.73 m2) 69 (34-100) 75 (25-97) 0.281 BMI (18.5-24.9) 30.7 27.3 0.108 Demographics LHPT PHPT Sex F: 20, M: 2 F: 18, M:4 Age 64.5 64.5 Li-treatment 22 / Earlier fracture 4 5 Osteopenia 12 8 Nephrolithiasis 2 6

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Table 4. The biochemical features, T-score and FRAX in patients with LHPT at the start and the end of the study,

demonstrated with median value and range.

* Two patients were excluded from the study, also one patient has not assessed FRAX/BMD. **The phosphate reference is influenced by diet, age and sex. The reference chosen was for women, as most of the patients are women.

Discussion

The present study found a decreased BMD in LHPT in comparison with PHPT, although the p-value (0.176) for T-score indicates that the result is not statistically significant. However, it is consistent with the higher prevalence of osteopenia among the LHPT patients found in this study. Generally, osteopenia and fractures were common in both groups. The FRAX assessment was also elevated (approximately 10%) among the LHPT patients, and somewhat reduced after 2 years, which could be related to surgical treatment, i.e. parathyroidectomy.

PTH levels did not differ apparently between the two groups (p=0.074), yet in the PHPT group, the PTH levels could rise dramatically compared to LHPT. Since PTH was slightly higher in the PHPT group, the phosphate is more cutback (p=0.043) because of PTH physiological actions. Results show moderate hypercalcemia in the LHPT group and more pronounced hypercalcemia in the PHPT group (p=0.001). Unlike the tightly maintained iCa concentration, tCa level is dependent on carrier proteins and anions in both intra- and extracellular, as well as ionic

complexes [28]. Therefore, iCa is a more robust parameter in diagnosing hyperparathyroidism or hypercalcemia. Interestingly, the tCa levels changed noticeably during the 2-year follow-up, suggesting there was a redistribution of the calcium dynamics in these patients. This could, like the reduction of PTH after 2 years, be the result of parathyroidectomy. Other features did not statistically change during the 2-year follow-up.

Biochemical features Start, n=10 2 years later, n=8* p- value

iCa (1.2-1.35 mmol/L) 1.4 (1.3-1.4) 1.4 (1.2-1.5) 0.419 tCa (2.18-2.6 mmol/L) 2.6 (2.5-2.7) 2.4 (2.3-2.7) 0.017 uCaE (2.5-8.0 mmol/ 24h) 3.2 (0.8-6.9) 2.6 (0.4-7.1) 0.429 PTH (1.6-6.9 pmol/L) 10.8 (7.6-19.1) 7.2 (5.3-17.3) 0.100 Phosphate (0.8-1.5 mmol/L)** 1 (0.7-1.7) 1 (0.8-1.1) 0.896 FRAX/T-score 9.7/-2.5 4.2/-2.2 Incalculable Vit-D (<75 mmol/L) 61 62 eGFR (mL/min/1.73 m2) 76.5 76

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13 The uCaE is often reduced in LHPT, which the present study also verified with 8 hypocalciuric LHPT patients. However, since not all patients are hypocalciuric, the diverse biochemical features in LHPT is further highlighted. The urinary calcium excretion in PHPT, was higher (p=0.003) and hypercalciuria was seen in 6 patients. This is consistent with the higher incidence of nephrolithiasis among PHPT patients as compared to LHPT patients (6:2).

Primary hyperparathyroidism and lithium-associated hyperparathyroidism

It is of significance to highlight the differences between PHPT and LHPT, perceived in the present study and concluded in several other studies [3,10,11,24,25]. In PHPT, PTH secretion is not suppressed by serum calcium because the production is autonomous (most likely an

adenoma). Therefore, both the PTH and iCa are elevated. PTH enhances calcium absorption in the intestines through vitamin D, calcium reabsorption in the kidneys and inhibits the renal reabsorption of phosphate [6]. The physiological actions of PTH result in an increased bone turnover, hypercalciuria and hypophosphatemia. The potential of these changes in calcium homeostasis is a ruction in BMD, as demonstrated in our results. In LHPT, the relationship between PTH and calcium suggests a right-shift in the set point, meaning that more calcium is needed to suppress PTH production. This means that, like PHPT, both PTH and calcium are simultaneously elevated, though not to the same extent as in PHPT but rather a moderate increase in or slightly above the reference range, with fluctuations in calcium not typical of PHPT. The right-shift also leads to hypocalciuria, which together with the increased intestinal calcium absorption and PTH actions leads to hypercalcemia. Since lithium inhibits cAMP formation, it is rather reduced or normal, compared to PHPT [25].

Nordenström et al. [29] observed that most of patients medicated with lithium (more than 10 years) showed higher levels of free calcium and/or PTH. Unlike Stancer and Forbath [24] (who distinguished LHPT from PHPT) the altered relationship between PTH and calcium that

Nordenström et al. reported, was consistent with primary HPT. The difference in results indicates that the biochemical features in both PHPT and LHPT are diverse, but could overlap. Future studies should analyze the differences between PHPT and LHPT in a large and

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Lithium-associated hyperparathyroidism, calcium and bone mineral density

The potential effects of lithium therapy on bone mineral density (BMD) and the risk of fracture examined in prior studies are contradictory. Some studies, including the present study, found that LHPT results in reduced bone mineral density [20,30], whilst other studies reported that lithium is associated with increased bone density [31] and reduced risk of fracture [32,33]. B. Liu et al. [34] concluded in a systematic review and meta-analysis of observational studies that lithium therapy is associated with a considerable reduced risk of fracture. Nordenström et al. [29] found a positive correlation between s-PTH and osteocalcin, a marker of bone formation, indicating increased bone mass, rather than decreased.

Mak et al. [5] observed a reduced 24h uCaE in LHPT patients. Calcium balance is affected by the daily calcium intake, absorption, and bone remodelling and could in part be measured by 24h urinary calcium. Therefore, a reduced 24h uCaE suggests a reduced net bone turnover. Mak et al. also found a normal s-ALP (a bone formation marker), which together with 24h uCaE further indicates reduced bone turnover. Lazarus et al. [36] found that lithium therapy enhances the intestinal absorption of calcium. An increased calcium uptake, together with a decreased urinary calcium excretion, could theoretically cause a moderate elevation in calcium levels independent of bone resorption.

To summarize, the effect of lithium enhances the intestinal calcium absorption and decreases urinary output of calcium. It also elevates PTH levels, amplifying its effects. Theoretically, the calcium would be trapped in the body and cause a severe hypercalcemia, but the clinical studies confirms otherwise. But then, what happens to the calcium? Future studies could research bone metabolism markers more closely, like ALP and osteocalcin, to learn if the calcium is indeed incorporated to the skeletal, or if it gets deposited or excreted elsewhere.

Lithium treatment and the kidney

Prior studies have associated lithium with a slight decreased renal function and a low incidence of end stage renal failure [14]. Seven of the examined patients had stage 3 kidney failure with an eGFR ranging from 34-56 mL/min/1,73 m2. Estimated GFR equalling 30-59 is considered as moderately reduced renal function, or stage 3 renal failure [37]. Renal insufficiency could lead to

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15 the development of secondary hyperparathyroidism, by a complex mechanism that is not entirely understood. Decreased phosphate excretion, leading to hyperphosphatemia, together with

decreased renal vitamin D synthesis, leading to reduced intestinal calcium absorption, both result in hypocalemia, which stimulates PTH secretion [7]. The higher incidence of renal dysfunction among LHPT patients may contribute to the increased risk in the development of osteoporosis. Indeed, the patients with renal dysfunction showed very high FRAX values, meaning they are at most risk of fracture in the coming years. The reduced kidney function could also explain the phosphate level, which is normal despite high levels of PTH, whose physiological action is to reduce phosphate.

Bipolar disease and risk of fracture

Both Mezuk et al. [38] and Su et al. [8], have investigated the association between BD and fractures, reporting respectively 20% and 17.6% increased risk of fracture associated with BD. The association of BD with an increased risk of fracture could be related to several factors, including medication, risk behaviour and poor diet. Patients with BD are commonly medicated with antipsychotics and benzodiazepines [8]. Prolactin-elevating antipsychotics are believed to increase the risk of osteoporosis [39] and other adverse effects of antipsychotics, such as over-sedation and postural hypertension, could exacerbate the risk of falling and fracture [40]. Henceforth, many factors in bipolar patients influence their BMD and risk of fracture, which should be considered while studying the relationship between lithium and BMD in a population.

Limitations

The present study among others, analyses older patients, with a median age of 64.5 years. The majority of patients were female. Age and gender are important factors which contribute to changes in calcium dynamics and reduced kidney function - postmenopausal women are particular prone to developing hypercalcemia, HPT and osteopenia [25]. The PHPT reference group were chosen to match the ages of patients in the LHPT group, to minimize the

confounding action of age.

The limitations of the present study include the limited number of included patients and the restricted follow-up period. To limit any confounders the studied population should be larger and

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16 observed for a longer period, where a reasonable time-period of clinical value could be five years. Another perspective is the selection of patients included in the study. If future studies were to select younger patients, recently diagnosed with BD and initiate the study at the time of

lithium administration, the significance of lithium on BMD would be better understood.

Conclusion

The present study shows that osteopenia and fracture could in fact be present among patients with LHPT, even though other studies suggest otherwise. There are a number of factors to account, such as the stability of the BD, renal function, age, sex and individual biochemical features. Since the diversity among LHPT patients is high, each case should be individually assessed for risk of developing hypercalcemia, osteopenia and fracture and followed-up routinely through DEXA and blood samples. In severe cases, subtotal parathyroidectomy should be

considered. This could help avert future discomfort from hypercalcemia and fracture.

Acknowledgement

I would like to express my sincere gratitude to my mentor Dr. Adrian Meehan, head of geriatric department in Örebro university hospital. Thank you for your patience, support, motivation and guidance throughout my research and thesis. I could not have asked for a better advisor and supervisor for my thesis.

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30. Christiansen C, Baastrup PChr, Transbøl I. Development of ‘Primary’ Hyperparathyroidism during Lithium Therapy: Longitudinal Study. Neuropsychobiology 1980; 6:280–3.

31. Zamani A, Omrani GR, Nasab MM. Lithium’s effect on bone mineral density. Bone 2009; 44:331–4.

32. Vestergaard P, Rejnmark L, Mosekilde L. Reduced Relative Risk of Fractures Among Users of Lithium. Calcif Tissue Int 2005; 77:1–8.

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Psychotropic Medications: A Population-Based Analysis. J Clin Psychopharmacol 2008; 28:384.

34. Liu B, Wu Q, Zhang S, Del Rosario A. Lithium use and risk of fracture: a systematic review and meta-analysis of observational studies. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 2019; 30:257–66.

35. Magno AL, Ward BK, Ratajczak T. The Calcium-Sensing Receptor: A Molecular Perspective. Endocr Rev 2011; 32:3–30.

36. Lazarus JH, Davies CJ, Woodhead JS, Walker DA, Owen GM. Effect of lithium on the metabolic response to parathyroid hormone. Miner Electrolyte Metab 1987; 13:63–6. 37. Njursvikt, hos vuxna - primär handläggning [Internet]. [cited 2019 May 26]; Available

from: https://www.internetmedicin.se/page.aspx?id=527

38. Mezuk B, Morden NE, Ganoczy D, Post EP, Kilbourne AM. Anticonvulsant Use, Bipolar Disorder, and Risk of Fracture Among Older Adults in the Veterans Health Administration. Am J Geriatr Psychiatry 2010; 18:245–55.

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Appendix 1.

Kriterier randomiserad LHPT studie

Urvalet är patienter från Örebro och Jönköping som uppfyller inklusions- och

exklusionskriterierna och som efter muntlig och skriftlig information accepterar att deltaga i studien.

Inklusionskriterier:

1. Konstaterad LiHPT definierat som joniserat/totalt/korrigerat serumkalcium över normalområdet med samtidig serumkoncentration av PTH över normalvärdet. 2. Ålder 20-75 år

3. Förstår information på svenska 4. Bor i eget boende

5. Har pågående litiumbehandling

Exklusionskriterier:

1. Kraftig hyperkalcemi (Serumkalcium > 3,0 mmol/l totalt/korrigerat eller > 1,50 mmol/l joniserat)

2. Ålder < 20 år eller > 75 år

3. Förstår ej fullgott information på svenska 4. Bor på institution

5. Komplicerande sjukdomar i hjärta-kärl, lungor, njurar (Cumulative Illness Rating Scale (CIRS))

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21

Appendix 2

För att kunna utföra FRAX måste man veta

1. Patientens ålder 2. Kön

3. Vikt 4. Längd

5. Tidigare fraktur

6. Höftfraktur hos föräldrar 7. Aktuell rökning

8. Pågående cortisonbehandling 9. Om patienten har reumatoid artrit

10. Om patienten har andra tillstånd som kan orsaka benskörhet 11. Om patienten tar 3 eller flera enheter alkohol per dag

12. Resultat från senaste DEXA; gå in på https://www.shef.ac.uk/FRAX/ . Välj ”Svenska” som språk. Därefter under rubrik ”Beräkningsverktyg” välj ”Europa > Sverige”. För in all information. Gör riskberäkning och skriva ut resultatet.

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22

Appendix 3

Ringa in korrekt alternativ!

Boendesituation Sammanboende 1 Ensamboende 2

Arbetet Arbetar heltid 1

Arbetar deltid 2 % =

Arbetssökande 3

Pensionär 4

Pensionär och arbetar 5 % = Hjälpinsatser (exv. Kommunen) Ja 1 Nej 2

Sjukdomar Diabetes Ja 1 Nej 2

Om ja Typ I 3

Typ II 4

Hypertoni Ja 1 Nej 2

Stroke eller TIA Ja 1 Nej 2

Ischaemisk hjärtsjukdom Ja 1 Nej 2

Stensjukdom Ja 1 Njursten 3 Nej 2

Gallsten 4 Osteoporos Ja 1 Nej 2

Tidigare operationer Paratyreoidea Ja 1 Nej 2

Tyreoidea Ja 1 Nej 2

Skelettfraktur med operation Ja 1 Nej 2

Skelettfraktur utan operation Ja 1 Nej 2

Annan Ja 1 Nej 2 Om ja, vad?

Fullständig läkemedelslista, inkl. vid behovsmedicinering och receptfria preparat

1. 2.

3. 4.

5. 6.

7. 8.

9. 10.

Vilket år började patienten med litiumbehandling? Hur länge har pat. ätit litium?

Obs! pat. kan ha haft uppehåll!

Om patienten är arbetsför: Hur många sjukdagar

uppskattningsvis har hon/han haft under senaste året?

1-14 dagar 15-30 dagar 31-90 dagar >90 dagar

Flertal frågor behövs för att utföra FRAX (vg se s.5 av mottagningsprotokoll). Planering - måldatum för nästa besök om 6 månader:

Figure

Table 2. The biochemical features and T-score in patients with LHPT and PHPT, presented with median value and  range
Table 4. The biochemical features, T-score and FRAX in patients with LHPT at the start and the end of the study,  demonstrated with median value and range

References

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