Risk factors for osteoporosis in inflammatory bowel disease patients

Inflammatory bowel disease (IBD) patients exhibit higher risk for bone loss than the general population. The chronic inflammation causes a reduction in bone mineral density (BMD), which leads to osteopenia and osteoporosis. This article reviewed each risk factor for osteoporosis in IBD patients. Inflammation is one of the factors that contribute to osteoporosis in IBD patients, and the main system that is involved in bone loss is likely RANK/RANKL/osteoprotegerin. Smoking is a risk factor for bone loss and fractures, and many mechanisms have been proposed to explain this loss. Body composition also interferes in bone metabolism and increasing muscle mass may positively affect BMD. IBD patients frequently use corticosteroids, which stimulates osteoclastogenesis. IBD patients are also associated with vitamin D deficiency, which contributes to bone loss. However, infliximab therapy is associated with improvements in bone metabolism, but it is not clear whether the effects are because of inflammation improvement or infliximab use. Ulcerative colitis patients with proctocolectomy and ileal pouches and Crohn’s disease patients with ostomy are also at risk for bone loss, and these patients should be closely monitored.     

Osteoporosis with low dose corticosteroids: contribution of underlying disease effects and discriminatory ability of ultrasound versus bone densitometry

OBJECTIVE: Corticosteroid use is associated with rapid bone loss, but the effect of low dose corticosteroids (CS) remains controversial and the extent to which increased fracture risk relates to quantitative effects, as reflected by change in bone mineral density (BMD), or to qualitative effects due to altered microarchitecture is unclear. Moreover the contribution of the underlying disease, for which CS are used, confounds the assessment of CS effects on bone. Our aim was to examine these effects of CS on bone. METHODS: We measured BMD, quantitative ultrasound (US), and clinical and radiological disease indices in 76 patients with rheumatoid arthritis (RA) treated with or without low dose CS. Disease effects were quantitated using the Health Assessment Questionnaire and radiological scores. RESULTS: BMD and US measures were significantly reduced in RA patients compared to age matched controls. Low dose CS use was associated with a further small but nonsignificant reduction in BMD, and US measures did not further discriminate CS effects on bone. Radiological score was an independent predictor of US measures, suggesting that in RA, calcaneal bone may reflect both systemic and local disease effects. CONCLUSION: US did not appear to discriminate effects of low dose CS on bone better than BMD. However, underlying RA disease effects on bone are detectable by US. Quantitative US should be investigated for its utility in assessing disease activity or progress in RA.     

Determinants of axial bone loss in rheumatoid arthritis

To assess mechanisms that cause generalized osteoporosis in rheumatoid arthritis (RA), we measured bone mineral density (BMD) by dual photon absorptiometry in the lumbar spine and femoral neck of 111 patients with RA. BMD was significantly reduced at both sites in these patients. Physical activity correlated significantly with BMD in patients with RA, and was found, by multiple regression analysis, to be a significant predictor of femoral bone density in female patients. Multiparity exerted a protective effect on lumbar bone density. Prednisolone (mean dosage 8 mg/day) was not associated with significantly increased bone loss in women, whereas higher dosages in men (mean 10.3 mg/day) were associated with increased lumbar bone loss. Reduced physical activity leading to a form of disuse osteoporosis appears to be an important factor in axial bone loss in RA.     

LIFE-STYLE, ENVIRONMENTAL AND MEDICAL FACTORS INFLUENCING PEAK BONE MASS IN WOMEN

The aim of this study was to assess which life-style factorswere associated with peak bone mass. One-thousand-two-hundred-and-twenty-sevenpre-menopausal women aged between 45 and 49 yr had their bonedensity measured at the hip and spine. In addition, these womenwere given a postal questionnaire asking about life-style factorsthat may be associated with bone mineral density (BMD). Usingstepwise multiple linear regression analysis we found that life-styleor environmental factors explained a small but significant proportionof the variation in BMD. Statistically significant associationsbetween anthropometric measures, exercise levels, fracture historyand BMD were found. We also observed a positive associationbetween self-reported numbers of miscarriages and BMD. Thiswork supports the conclusions of smaller studies that risk factoranalysis explains only a small amount of the variance in BMD. KEY WORDS: Bone mineral density, Risk factors, Early pregnancy loss, Weight, Height, Peak bone mass     

Increase in bone mineral density and its effect on fracture risk

Over the past 10 years a number of clinical trials have evaluated several agents for treatment and prevention of osteoporosis, and demonstrated that these agents can increase bone mineral density (BMD) and reduce the incidence of fracture. Although the relationship between antifracture efficacy and changes in BMD varies greatly among reports, all of them suggest the presence of antifracture effect that is mediated by factors other than BMD. Fracture risk is associated with bone strength and nonskeletal risk factors such as the propensity to fall. Bone strength is primarily determined by BMD, but bone quality such as bone remodeling, structural and material properties is also an important determinant of bone strength. Some of the agents for osteoporosis treatment might provide the atifracture effect mainly through the improvement of bone quality. The mechanism how the reduction in fracture risk is achieved deserves further studies.     

Effects of asthma and asthma therapies on bone mineral density.

With improvements in techniques for measuring bone mass, interest and concern have increased about the effects of asthma therapies, particularly corticosteroids, on bone mineral density. Whether asthma itself causes bone loss remains unclear. Studies evaluating the effect of asthma therapies on bone mineral density are often difficult to interpret because of methodologic problems. These studies show that oral corticosteroids are associated with a reduction in bone mineral density and an increased risk of fracture. Studies evaluating the effects of inhaled corticosteroids on bone mineral density provide conflicting data, but there is increasing evidence that inhaled corticosteroids may have an adverse effect on bone. However, the benefits of inhaled corticosteroids in the treatment of asthma remain far greater than the risks. The data for the effects of other asthma therapies on bone mineral density are limited.     

Change in bone mineral density in patients with rheumatoid arthritis during the first decade of the disease.

OBJECTIVE: Rheumatoid arthritis (RA) has been reported to be associated with bone loss during the first years of the disease. The magnitude of this problem after the initial years has not yet been evaluated. In the present study, the change in bone mineral density (BMD) in patients with recent-onset RA as well as the effects of inflammation, mobility, and the use of prednisone on this change were studied in the first decade of the disease. METHODS: BMD was measured twice in 76 RA patients with mean disease durations of 2.35 years at the first BMD measurement and 8.90 years at the second BMD measurement. BMD was measured in both hips using dual x-ray absorptiometry. Results were expressed as mean +/- SEM Z scores (using age- and sex-matched reference values) and as mean +/- SEM percent change in BMD (in gm/cm2) per year. The effects of inflammation, mobility, and the use of prednisone on change in BMD were evaluated using multiple linear regression analyses. RESULTS: At the first BMD measurement, RA patients had lower BMD compared with the reference values (Z score -0.42+/-0.11, 95% confidence interval [95% CI] -0.64, -0.20). Between the 2 measurements, we observed a small decrease in BMD of -0.28+/-0.11%/year (95% CI -0.07 to -0.49). However, the rate of bone loss was smaller than expected. The Z score increased by 0.13+/-0.05 between the 2 BMD measurements (95% CI 0.02, 0.23). Only the use of prednisone was significantly associated with increased bone loss. In a separate analysis that included only postmenopausal women, increased physical activity and longer time since menopause were both associated with decreased bone loss. In this subgroup of patients, the use of prednisone was significantly associated with increased bone loss as well. A high erythrocyte sedimentation rate was associated with increased bone loss, but this did not reach statistical significance. CONCLUSION: After the initial years of the disease, bone loss in RA patients is lower than expected compared with age- and sex-matched reference values. Postmenopausal RA patients with low levels of physical activity are at increased risk of losing bone. Use of prednisone was the only variable consistently associated with reduction in BMD in RA patients.     

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.     

Bone density reduction in patients with Crohn disease and associations with demographic and disease variables: cross-sectional data from a population-based study.

BACKGROUND: The extent of bone density reduction in patients with Crohn disease is still being debated. The aim of this study was to examine bone mineral density (BMD) and factors associated with reduced BMD in a representative population of patients with Crohn disease aged between 20 and 70 years. METHODS: BMD (using dual energy X-ray absorptiometry) was measured in spine and hip in 55 patients with Crohn disease recruited from the entire Crohn population (n = 96) in a defined area of southern Norway. Demographic and clinical data were also collected. The patients were compared with 52 age- and gender-matched healthy controls. Potential demographic and disease-related factors associated with BMD reduction were statistically tested with bi- and multivariate analyses. RESULTS: The BMD reduction in patients with Crohn disease was 7.1% (P = 0.02) in spine L1-4, 6.1% (P = 0.08) in femoral neck and 8.4% (P = 0.02) in total hip as compared with the controls. In total hip and femoral neck, age, body weight and gender were independently associated with reduced BMD, but in the spine only body weight. Among the disease-related variables, only ever use of prednisolone was independently associated with reduction in BMD but this only in the femoral neck. CONCLUSIONS: The spine and hip BMD reduction of 6%-8% is similar to that found in a comparable population-based study performed in another area in Norway. Among the disease-related variables tested for, only the use of prednisolone was independently associated with BMD reduction. However, the BMD reduction measured in this study indicates that disease-related mechanisms are involved.     

Soy protein intake and bone mineral density

It has been reported that soy protein prevents the bone loss in in vitro and in vivo studies. Isoflavones contained in soy stimulate the protein synthesis and the expression of alkalinephophatases in osteoblasts. Additionally food enriched isoflavones prevented the reduction of bone mineral density (BMD) in ovariectomised rats or mice. We demonstrated the association of soy protein intake with the increase of BMD and the inhibition of urinary deoxypyridinoline. Interventional studies also exhibited the prevention of the reduction of BMD. However double-blind, randomized case-control trial does not support the hypothesis that use of soy protein supplement containing isoflavones improve BMD. We need further to detect the more potent isoflavones on bone metabolism.     

Voluntary weight reduction in older men increases hip bone loss: the osteoporotic fractures in men study

To test the hypothesis that weight loss in older men is associated with increased rates of hip bone loss regardless of adiposity and intention to lose weight, we measured body weight, body composition, hip bone mineral density (BMD), and intention to lose weight in a cohort of 1342 older men enrolled in the Osteoporotic Fractures in Men (MrOS) study and followed them prospectively for an average of 1.8 yr for changes in weight and BMD. The adjusted average rate of change in total hip BMD was 0.1%/yr in men with weight gain, -0.3%/yr in men with stable weight, and -1.4%/yr in men with weight loss (test for trend, P < 0.001). Higher rates of hip bone loss were observed in men with weight loss regardless of category of body mass index, body composition, or intention to lose weight. Even among obese (body mass index, > or =30 kg/m2) men trying to lose weight, those with documented voluntary weight reduction experienced an increase in hip bone loss (average rate of change in total hip BMD, 0.5%/yr in those with weight gain, -0.1%/yr in those with stable weight, and -1.7%/yr in those with weight loss; test for trend, P < 0.001). Older men who experience weight loss have increased rates of hip bone loss, even among overweight and obese men undergoing voluntary weight reduction.     

Hip mineral density in females with a recent hip fracture.

To evaluate the role of local bone mineral density (BMD) in the etiology of hip fractures, we measured the hip BMD using dual photon absorptiometry in 29 females who had recently suffered a hip fracture associated with minimal or moderate, but not major, trauma and compared their BMD to those of 14 young normal females, 58 early postmenopausal normal females, 13 age-matched normal females, and 114 spinal osteoporotic females without a hip fracture. Hip-fractured patients had a BMD significantly lower (P less than 0.001) than that of all other studied groups, suggesting that a low hip BMD is associated with hip fracture risk. A femoral neck BMD below 0.75 g/cm2 suggests an increased likelihood for developing a hip fracture. Peak BMD was measured at 1.03 g/cm2, a value comparable to published normative data. Thus, a loss in hip BMD of approximately 30% from peak mineral density appears necessary before a hip fracture may occur after moderate trauma.     

Antifracture efficacy of antiresorptive agents are related to changes in bone density

There is a current debate about the extent to which antifracture efficacy of antiresorptive drugs are related to changes in bone mineral density (BMD). In vitro studies show that most of the variability in bone strength is related to BMD, and prospective studies have shown that low BMD is an important predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a reduction in activation frequency or resorption depth would lead to fewer (and/or shallower) resorption sites and refilling of existing sites initially. There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and this may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural elements would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term antifracture efficacy of antiresorptive drugs will depend on the extent to which treatment can increase and maintain BMD. To examine this issue, we compiled data from clinical trials of antiresorptive agents and plotted the relative risk of vertebral fractures against the average change in BMD for each trial. The confidence intervals are large for individual trials, and there was substantial variability in antifracture efficacy at any given level of change in BMD. Overall, however, trials that reported larger increases in BMD tended to observe greater reductions in vertebral fracture risk. Poisson regression was used to quantify this relationship. The model predicts that treatments that increase spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings are consistent with the short-term predictions of the conceptual model and with reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD technology.     

Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir.

BACKGROUND AND OBJECTIVES: To determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART). METHODS: Analyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients. RESULTS: Average lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P = 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31 z-score per year; P < 0.001). Lower initial z-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P = 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P = 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P = 0.04), this effect was abrogated in a multiple linear regression analysis (P = 0.11) with lowest BMI remaining significant (P = 0.04). CONCLUSIONS: We found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an individual's initial z-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spine z-score.     

Bone disease in patients with haemophilia A and B – where are we now?

It is evident that haemophilia A and B are associated with decreased bone mass in both adults and children. Decreased physical activity and vitamin D deficiency are some of the major factors leading to bone loss. Hepatitis C virus (HCV) infection may also contribute to low bone mineral density (BMD). However, definite conclusions regarding the exact prevalence and pathogenesis of osteoporosis cannot be conducted yet, due to the small sample size and significant heterogeneity among studies. Discordant findings with regard to the skeletal site of low BMD have also been reported. Furthermore, data on fracture risk are sparse. The use of the Fracture Risk Assessment Tool (FRAX) for assessing fracture risk, regular BMD assessment at the age of 25 and thereafter, careful evaluation of risk factors associated with bone loss and optimal calcium and vitamin D intake are recommended. Long‐term prophylactic factor replacement therapy, resistance exercise and bisphosphonates, in severe cases of increased fracture risk, can prevent bone loss.     

A potential primate model for bone loss resulting from medical oophorectomy or menopause

This study examined the potential use of the GnRH agonist-treated female monkey as a model for bone loss after medical oophorectomy or the onset of menopause in women. Three female rhesus monkeys (13-16 yr of age) were treated continuously for 10 months with 25 micrograms/day GnRH agonist using osmotic minipumps. All three animals exhibited normal menstrual cycles before treatment. Within 5 weeks of the beginning of GnRH agonist treatment, serum progesterone and estradiol concentrations had fallen to low values and did not rise significantly during the remaining treatment period. The decline in ovarian steroidogenesis was correlated with a reduction in bone mineral density (BMD; bone mineral content/bone width) of the caudal vertebrae and humerus. The reduction of BMD of the caudal vertebrae occurred gradually. The downward trend was evident during the first 3 treatment months, but did not fall significantly below pretreatment levels until 9 months of GnRN agonist treatment. The overall decline in BMD for the caudal vertebrae was approximately 14% after 9 months of GnRH agonist treatment. The measured decline in BMD of the humorous was 11%. Serum osteocalcin levels rose more than 10-fold above pretreatment values between 4 and 7 months of GnRH agonist treatment before declining to levels that approached pretreatment concentrations between 8 and 10 months of treatment. Menstrual cycles were reinitiated within 4 weeks after the termination of treatment, as shown by luteal phase increases in serum progesterone concentrations. BMD of the humerus and caudal vertebrae remained subnormal 2 months posttreatment, but by 5 months had recovered to near-pretreatment values. These data suggest that ovarian hormone deprivation induced by GnRH agonist administration is associated with a decline in BMD in female monkeys, and that this animal model may be an excellent model for postmenopausal bone loss or bone reduction resulting from medical oophorectomy. The GnRH agonist-treated monkey also has the potential to be developed as a model for type I postmenopausal osteoporosis.     

Bone mineral density in lymphangioleiomyomatosis

Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women that is characterized by cystic lung lesions, is frequently treated with antiestrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether antiestrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD was found in 70% of the patients and correlated with severity of lung disease and age. Greater severity of lung disease, menopause, and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, we found similar rates of BMD decline in progesterone-treated (n = 122) and untreated patients (n = 89). After similar adjustments, we found that bisphosphonate-treated patients (n = 98) had lower rates of decline in lumbar spine BMD (-0.004 +/- 0.003 vs. -0.015 +/- 0.003 gm/cm(2), p = 0.036) and T-scores (-0.050 +/- 0.041 vs. -0.191 +/- 0.041, p < 0.001) than untreated patients (n = 113). We conclude that abnormal BMD was frequent in LAM. Progesterone therapy was not associated with changes in BMD; bisphosphonate therapy was associated with lower rates of bone loss. We recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.     

Vitamin D receptor and aromatase gene interaction and bone mass in older African-American women

Aromatization of androgens by the CYP19 gene product, aromatase, is the major source of endogenous estrogen in postmenopausal women. We determined whether an Arg(264)Cys polymorphism in the CYP19 gene is associated with bone mineral density (BMD) and bone loss in older women. Because vitamin D regulates CYP19 gene expression, we also tested for an interaction with a translation start site polymorphism in the vitamin D receptor (VDR) gene. Hip BMD was measured twice, an average of 1.9 years apart, in 100 African-American women aged > or =65 years. Neither polymorphism alone was significantly associated with BMD or bone loss. BMD measurements in women with the less frequent allele at both loci were 0.5 to 1.3 SD lower than in women with neither or only a single rare allele (P <.001 for interaction). These women also experienced more rapid hip bone loss than other women (P <.05 for interaction). We conclude that VDR and CYP19 gene polymorphisms may jointly influence bone mass and the rate of bone loss in older African-American women.     

Bone loss at the femoral neck in premenopausal white women: effects of weight change and sex-hormone levels

To investigate whether bone loss occurs in the premenopause, we measured the bone mineral content (BMC), bone mineral density (BMD), and bone area in the spine (L2-L4), femoral neck, and total hip, as well as the sex hormone levels of 130 healthy premenopausal white women (age, 31-50 yr) at least three times over 1-9 yr. We found an increase in all three bone measurements at the spine but no change in volumetric density. Neither could we detect any age-related changes in any of the three measurements in the total hip. In contrast, we detected a significant decrease in femoral neck BMD over time, due to a decrease in BMC and increase in bone area. Greater loss in femoral neck BMD was associated independently with weight loss and lower levels of estrone sulfate or E2. Separating the women into those with FSH spikes (>20 IU/liter) and women with consistently low FSH, we found the latter group had smaller decrease in BMD and that the decrease was due less to a decline in BMC and more to an increase in bone area. In summary, femoral neck BMD decreases in premenopausal women, particularly those with lower levels of estrogens resulting from slowing ovarian function despite regular menses. This decrease can be offset by more rapid weight gain.     

Primary hyperparathyroidism and the skeleton

Today, primary hyperparathyroidism (PHPT) in the developed countries is typically a disease with few or no obvious clinical symptoms. However, even in the asymptomatic cases the endogenous excess of PTH increases bone turnover leading to an insidious reversible loss of cortical and trabecular bone because of an expansion of the remodelling space and an irreversible loss of cortical bone due to increased endocortical resorption. In contrast trabecular bone structure and integrity to a large extent is maintained and there may be a slight periosteal expansion. Most studies have reported decreased bone mineral density (BMD) in PHPT mainly located at cortical sites, whereas sites rich in trabecular bone only show a modest reduction or even a slight increase in BMD. The frequent occurrence of vitamin D insufficiency and deficiency in PHPT and increased plasma FGF23 levels may also contribute to the decrease in BMD. The effect of smoking is unsolved. Epidemiological studies have shown that the relative risk of spine and nonspine fractures is increased in untreated PHPT starting up to 10 years before the diagnosis is made. Successful surgery for PHPT normalizes bone turnover, increases BMD and decreases fracture risk based on larger epidemiological studies. However, 10 years after surgery fracture risk appears to increase again due to an increase in forearm fractures. There are no randomized controlled studies (RCTs) demonstrating a protective effect of medical treatment on fracture risk in PHPT. Less conclusive studies suggest that vitamin D supplementation may have a beneficial effect on plasma PTH and BMD in vitamin D deficient PHPT patients. Hormone replacement therapy (HRT) and maybe SERM appear to reduce bone turnover and increase BMD. However, their nonskeletal side-effects preclude their use for this purpose. Bisphosphonates reduce bone turnover and increase BMD in PHPT as in osteoporosis and may be a therapeutical option in selected patients with low BMD. Obviously, there is a need for larger RCTs with fractures as end-points that appraise this possibility. Calcimimetics reduce plasma calcium and PTH in PHPT but has no beneficial effect on bone turnover or BMD. In symptomatic hypercalcaemic PHPT with low BMD where curative surgery is impossible or contraindicated a combination of a calcimimetic and a bisphosphonate may be an undocumented therapeutical option that needs further evaluation.