Bone and joint quality remains impaired in long-term controlled acromegaly: an HR-pQCT study.

Acromegaly is a rare endocrine condition [ 1 , 2 ] characterized by hypersecretion of growth hormone (GH) from a benign pituitary adenoma [ 3 ], leading to several severe complications [ 4 ], both distressing for patients [ 5 ] and costly for health care systems [ 6 ]. No complication, however, is more deleterious to patients' quality of life (QoL) than the musculoskeletal complications of acromegaly [ 7 , 8 ], which may progress over time, irrespective of disease control [ 9 , 10 ].

Due to the trophic effects of GH and insulin-like growth factor 1 (IGF-I) on chondrocytes [ 11 ], acromegaly leads to cartilage growth, which causes periarticular ligament laxity, joint instability, increased mechanical stress, cartilage ulceration, and destruction [ 12 ], ultimately leading to manifest osteoarthritis [ 10 , 12-15 ]. Unlike primary osteoarthritis, however, acromegalic arthropathy is characterized by preserved or widened joint spaces with severe osteophytosis [ 12 , 15-19 ]. High-resolution peripheral quantitative computed tomography (HR-pQCT) has been used extensively to assess joint pathology in rheumatological disorders, as it provides detailed images of peripheral periarticular structures and enables precise quantification of structural abnormalities such as erosions and osteophytes [ 20 ], but also joint space volume [ 21 , 22 ]. While osteoarthritis with severe osteophytosis is a well-established hallmark of acromegaly [ 12 , 13 , 15-19 ], this joint pathology has thus far not been studied using HR-pQCT.

The effects of GH and IGF-I excess on the skeleton are manifold [ 11 ], with the net result of compromised trabecular structure and quality but preserved—or even increased—areal bone mineral density (aBMD) on dual X-ray absorptiometry (DXA) imaging [ 11 , 23-32 ]. The compromised quality of the trabecular bone compartment leads to a higher risk of vertebral fractures [ 10 , 11 , 24 , 27 , 29 , 33-35 ], whereas the data on appendicular skeletal fractures are more divergent, with both reduced [ 10 , 36 ] and increased [ 37 , 38 ] risk being reported. Bone turnover markers have been found to be increased in active acromegaly [ 27 ], whereas sclerostin—an inhibitor of bone formation secreted by osteocytes—has shown a more divergent pattern as relates to acromegaly activity, with both significantly higher and lower values being reported [ 33 , 39 , 40 ], and without a clear relation to the occurrence of vertebral fractures [ 33 ]. Since aBMD measurements correlate poorly with bone quality in patients with acromegaly [ 11 , 27 , 30-32 ], alternate means for its assessment have been explored, including trabecular bone score [ 26 , 28 , 41 ], quantitative computed tomography (QCT) [ 30 ], cone beam tomography [ 42 ], HR-pQCT [ 23 , 31 , 32 ] and bone impact microindentation [ 43 ]. HR-pQCT provides high-resolution images of peripheral skeletal structures, with its smaller voxel size of 82 μm and shorter acquisition times setting it apart from MRI and QCT imaging modalities, and HR-pQCT is considered the gold standard for imaging peripheral bone microarchitecture [ 20 , 44 ].

Bone impact microindentation, a minimally invasive procedure using a hand-held stylus to assess cortical bone structural integrity [ 45 ], has shown promise as a supplement to standard-of-care bone evaluation, since it provides information on in vivo bone quality and mechanical properties at the tissue level [ 45 ] not otherwise attainable. No studies have yet examined how these modalities intercorrelate with aBMD in patients with long-term, well-controlled acromegaly.

We aimed to study joint features using HR-pQCT and perform an integrated assessment of bone quality using HR-pQCT, DXA, bone impact microindentation, and vertebral fracture assessment (VFA), in patients with long-term controlled acromegaly compared to matched healthy controls.

Materials and Methods

The study was conducted as a cross-sectional study, and the main outcomes of interest were the HR-pQCT-derived joint parameters (joint space volume, joint space width, and osteophyte number and diameter), with bone impact microindentation, DXA parameters, and bone-related HR-pQCT parameters (trabecular and cortical indices, specifically trabecular vBMD, number, thickness and separation, and cortical vBMD, porosity, and cortical pore diameter) as secondary outcomes.

Participants

Participants with acromegaly were recruited from the outpatient clinic of Aalborg University Hospital, North Denmark Region, with the following inclusion criteria: Verified acromegaly diagnosis, in biochemical remission at the time of the study; ability to provide informed consent; preserved ambulatory function; stable replacement therapy of any pituitary deficiency.

The exclusion criteria were: diagnosis of osteoporosis necessitating medical treatment as per local guidelines [ 46 ]; conditions associated with secondary osteoporosis (severe kidney or liver dysfunction, malabsorption, multiple myeloma, primary hyperparathyroidism); treatment with drugs that impair bone quality; diagnosis of joint diseases unrelated to acromegaly; active drug or alcohol abuse; pregnancy; known allergy/hypersensitivity to local anesthetics or disinfectant, or other physical factors that render the subject unable to participate. Although a risk factor for secondary osteoporosis [ 47 ], diabetes was not a criterion for exclusion due to its close association with acromegaly [ 4 ]. For each participant with acromegaly, one sex- and age-matched control was identified through a database of volunteer participants.

Participants' weight and height were measured, and a smoking and diabetes history was recorded. For the acromegaly patients, disease-specific data on hormonal levels and acromegaly treatment were obtained from medical records. Biochemical disease control was defined as having an IGF-I standard deviation score ≤ 2 at the latest measurement.

All participants signed a written informed consent form before taking part in the study. The study was conducted in accordance with the Helsinki declaration, approved by the local ethics committee (case no. N20220041) and prospectively registered with www.clinicaltrials.gov (ID: NCT05752825 ).

Study procedures

HR-pQCT

The non-dominant distal radius and tibia were scanned with XtremeCT I (ScanCo Medical AG, Brüttisellen, Switzerland), as were the wrist joint and the second and third metacarpophalangeal (MCP) joints. For joint imaging, the reference line was placed at the midpoint of the radial articular surface curvature, and the concave articular surface at the base of the second proximal phalanx, respectively ( Fig. 1 ). Two stacks of 110 slices each were recorded at each site, corresponding to 9.02 mm on each side of the reference line.

Based on the scans, bone and joint parameters were calculated using the software and scripts supplied by the manufacturer, based on a recent consensus statement [ 22 ].

The cortical bone compartments of the distal tibia and radius were analyzed for area (CtA), perimeter (CtPm), volumetric bone mineral density (CtvBMD), porosity (CtPo), pore diameter (CtPoDm), and thickness (CtTh), whereas the trabecular compartments were assessed for area (TbA), vBMD (TbvBMD), trabecular number (TbN), thickness (TbTh), separation (TbS), and bone volume/tissue volume ratio (BV/TV).

A daily quality control program was in place using a standardized phantom. The coefficients of variation (CV) were low (between 0.02% and 4.35%) [ 48 ].

For analysis of joint space, the wrist joint was divided into 2 separate entities, ie, the radioscaphoid and radiolunate joint, and the wrist and MCP joints were assessed for joint space width (JSW), volume (JSV), maximum and minimum joint space width (JSW max and JSW min ). Based on these parameters, the joint space asymmetry (JSW.AS) was calculated as the ratio between JSW max and JSW min [ 21 ]. The periarticular regions of the radius and the second and third MCP joints were analyzed for the presence, number, maximum size, and anatomical distribution of erosions and osteophytes, using the method described by Stach et al [ 49 ]. An example of the joint analysis result is shown in Fig. 2 .

DXA and VFA

Areal BMD was assessed for the lumbar spine and the hip using the same device (Hologic, Inc., Marlborough, MA, USA), and the T-score for each site was calculated.

Daily quality control procedures, including a standardized phantom, were in place, and the CV was low (1.09% at lumbar spine, 1.15% at total hip, and 1.77% at femoral neck [ 50 ]).

Furthermore, vertebral fracture analysis (VFA) of the lumbar and thoracic spine was performed to assess any vertebral fractures using the semiquantitative method described by Genant et al [ 51 ]. VFA images were evaluated by 2 of the investigators (C.R. and J.D.), and the results were compared. Any disagreements were settled by consensus. Based on the VFA results, each participant's spinal deformity index (SDI) was calculated as the sum of Genant grades [ 52 ].

Bone impact microindentation

Using an OsteoProbe® (Active Life Scientific, Santa Barbara, CA, USA), bone integrity was assessed at the tissue level via microindentation of the medial non-dominant tibia. With the participant in a supine position, the indentation site was identified as the midpoint between the medial malleolus and the tibial plateau, using a measuring tape. After skin disinfection, an intracutaneous and periosteal local anesthetic was applied. The tip of the OsteoProbe stylus was inserted through the skin perpendicular to the tibia, and a series of indentations was performed, as guided by the hardware supplied by the manufacturer. A minimum of 8 indentations was made, and the stylus tip was moved slightly between each indentation. Finally, a series of indentations was performed on a polymer reference block, after which the participant's bone material strength index (BMSi) was calculated and presented on the system supplied by the manufacturer.

Interobserver variability was investigated through repeated measures in 12 participants, yielding a CV of 10.1%.

Biochemical measurements

With the participant fasting, blood samples were drawn and stored at −80°C until study termination. Subsequently, the samples were analyzed for parathyroid hormone (PTH), 1,25-Vitamin D, sclerostin, collagen I beta-crosslaps (CTx), and procollagen I N-terminal propeptide (P1NP).

Questionnaires

Self-reported lower limb joint pain and stiffness were assessed using the Danish version of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale [ 53 ] including a total of 24 questions across 3 domains (pain, stiffness, and activities of daily living impairment). Scores range from 0 to 96, with higher scores indicating more pain and stiffness. Participants with acromegaly also completed the Danish version of the AcroQoL questionnaire [ 54 ], with higher scores reflecting better QoL.

Statistical analysis

The distribution of continuous data was assessed visually using QQ-plots. Normally distributed continuous data were presented as mean (SD) and non-normally distributed data as median [IQR]. For group comparison, dichotomous data were analyzed using the Chi-square test, normally distributed data using the two-sample t -test, and non-normally distributed data using the rank-sum test. Log-normally distributed data were analyzed using the two-sample t -test and the obtained estimates back-transformed using exponentiation. Regression analyses for dichotomous, count, and continuous outcomes were performed as binary (log-link), negative binomial, and linear regression, respectively. Linear regression model validity was assessed using Q–Q-plots of the residuals, and the likelihood ratio test for overdispersion was used to assess negative binomial regression model validity. Due to their well-established deleterious effect on bone health [ 47 , 55 ], regression analyses for bone-related outcomes were adjusted for smoking and diabetes status, whereas those for joint-related outcomes were not. A 5% significance level was assumed. Data analysis was performed using STATA v. 17 for Mac.

Results

The study included 17 patients with acromegaly (mean age 61.8 ± 11.9 years, 65% female) and 17 matched controls (mean age 61 ± 11.7 years, 65% female). The majority of women were postmenopausal, with only 2 (18%) and 3 (27%) premenopausal women in the acromegaly and control groups, respectively.

No participants with acromegaly had Multiple Endocrine Neoplasia 1-associated acromegaly.

Participants with and without acromegaly were similar as regards body mass index (BMI), menopausal status, diabetes status, and diabetes duration. A significantly larger proportion of controls had never smoked (88.2% vs 35.3%, P = .004), whereas the mean number of pack years among smokers was similar ( P = .18) ( Table 1 ).

All participants with acromegaly were treated surgically, and 9 received adjuvant medical therapy, including somatostatin analogs ( n = 8), pegvisomant ( n = 1) and cabergoline ( n = 1). Biochemical control of acromegaly was achieved in all patients, with a mean IGF-I standard deviation score of 1.2 (±1.6) at the latest outpatient visit. Four participants with acromegaly received hormone replacement therapy on one or more axes, of which one was treated with sex hormone replacement. All other pituitary axes were intact, and the substituted hormones were within normal levels (data not shown). The mean AcroQoL score was 80.9 (±14.3) points ( Table 1 ).

Joint-related parameters

Participants with acromegaly had a significantly higher mean JSW max of the MCP joints than controls (MCP2: 2.92 (0.14) mm vs 2.80 (0.15) mm, P = .037; MCP3: 2.85 (0.13) mm vs 2.68 (0.17) mm, P = .004), and a significantly larger proportion of patients had at least one osteophyte in the third MCP joint (50% vs 11.8%, P = .017). Participants with acromegaly tended to have a higher median number of osteophytes at all joint sites ( Table 2 ). In regression analyses, the total number of osteophytes correlated positively with the presence of acromegaly ( β : .84 [0.11; 1.57], P = .024) ( Table 3 ) and with increasing age in the acromegaly group ( β : .08 [0.04; 0.12], P < .001), but not the control group ( β : .03 [−0.013; 0.07], P = .178) ( Fig. 3A ). Both the number and size of osteophytes at the third MCP joint correlated positively with the presence of acromegaly ( β : 1.79 [0.27; 3.32], P = .021, and β : .28 [0.03; 0.52], r 2 = 0.16, P = .034, respectively) ( Table 3 ).

Participants with acromegaly had significantly higher (ie, worse) median WOMAC-scores than controls (17.0 vs 1.0, P = .002).

The remaining HR-pQCT-derived joint measurements were similar between the 2 groups ( Tables 2 and 3 ), as were the anatomical distribution and Stach grade of osteophytes and erosions (data not shown).

Bone-related parameters

A significantly larger proportion of participants with acromegaly had at least one vertebral deformity (Genant grade ≥1), as demonstrated by VFA (15 vs 8, P = .01), a higher mean number of deformed vertebrae per participant (2.1 (±1.3) vs 0.7 (±0.8), P < .001), and a higher mean SDI (2.6 (±2.0) vs 1.3 (±1.5), P = .04) ( Table 4 ). Participants with acromegaly had significantly lower trabecular vBMD at both sites (radius: 114.8 (±40.7) vs 150.3 (±31.9) mg/cm 3 , P = .008, tibia: 129.3 (±40.2) vs 166.2 (±22.0) mg/cm 3 , P = .002) and BV/TV (radius: 0.10 (±0.03) vs 0.13 (±0.03), P = .008, tibia: 0.11 (±0.03) vs 0.14 (±0.02), P = .002), as well as a higher trabecular separation (radius: 0.58 (±1.40) vs 0.42 (±1.15) mm, P = .001, tibia: 0.50 (±0.15) vs 0.41 (±0.062) mm, P = .023). Likewise, the acromegaly group had significantly lower mean trabecular thickness of the tibia (0.056 (±0.01) mm vs 0.064 (±0.01) mm, P = .005), and fewer trabeculae per millimeter at the radial site (1.63 (±0.49) vs 2.11 (±0.25) mm −1 , P = .001) ( Table 4 ).

There were no statistically significant differences in HR-pQCT estimates between participants with and without vertebral deformities (data not shown).

In regression analyses with adjustment for confounders (smoking and diabetes status), the risk of having at least one vertebral deformity was higher in the acromegaly group (RR: 1.99 [1.17; 3.38], P = .011 (unadjusted P = .021)), as was the number of vertebral deformities ( β : 1.10 [0.35; 1.85], P = .004) and the SDI ( β : 1.34 [0.26; 2.42], r 2 = 0.36, P = .017) ( Table 3 ). When including only more severe vertebral deformities (Genant grade ≥ 2), no differences were found between groups (data not shown).

After adjustment for confounders, trabecular number and separation of the distal radius correlated negatively ( β : −.51 [−0.87; −0.15], r 2 = 0.30, P = .008) and positively ( β : .21 [0.04; 0.38], r 2 = 0.30, P = .016) with the presence of acromegaly, respectively ( Table 3 ). Trabecular number and vBMD correlated negatively with age in the acromegaly group ( β : −.03 [−0.05; −0.01], r 2 = 0.50, P = .004 and β : −1.95 [−3.52; −0.37], r 2 = 0.31, P = .02, respectively), while the correlation with trabecular separation was positive ( β : .01 [0.00; 0.02], r 2 = 0.48, P = .01) ( Fig. 3B-3D ). No such associations reached statistical significance in the control group.

As regards the cortical measurements, participants with acromegaly had significantly lower cortical porosity of the tibia than controls (0.06 (±0.02) % vs 0.08 (±0.03) %, P = .028), but there were no other statistically significant differences regarding cortical bone measurements ( Table 4 ).

No statistically significant differences were found regarding mean DXA-derived T -scores of the hip (−0.4 (±1.0) in both groups, P = .97) or spine (0.4 (±2.1) vs −0.1 (±1.3), P = .42), BMSi (76.8 (±9.2) vs 82.0 (±5.4), P = .059), bone turnover markers (CTX: 0.3 (±0.3) ng/mL in both groups, P = .77, P1NP: 56.8 (±22.4) vs 64.4 (±27.6) ng/mL, P = .38, sclerostin: 116.5 (±46.6) vs 136.8 (±36.5) pmol/L, P = .17) or markers of calcium and phosphate metabolism (25-hydroxy vitamin D: 101 (±31.0) vs 92.8 (±37.0) nmol/L, P = .59, 1,25-hydroxy vitamin D: 61.8 (×/1.5) vs 52.3 (×/1.3) pg/mL, P = .14 and PTH: 5.2 (±1.8) vs 5.1 (±1.5) pmol/L, P = .81).

In a subgroup analysis within the acromegaly group, comparing medically treated and surgically cured patients, joint-related HR-pQCT parameters exhibited no statistically significant differences (data not shown).

As for the bone-related HR-pQCT parameters, trabecular indices were significantly more deteriorated in medically treated patients. They had lower tibial vBMD ( β : −48.79 [−85.20; −12.39], r 2 = 0.44, P = .01), lower tibial BV/TV ( β : −.04 [−0.07; −0.01], r 2 = 0.44, P = .01), lower radial and tibial trabecular number (radius: β : −.65 [−1.11; −0.20], r 2 = 0.56, P = .01; tibia: β : −.51 [−1.00; −0.01], r 2 = 0.45, P = .04) and higher trabecular separation (radius: β : .29 [−0.09; −0.50], r 2 = 0.54, P = .01; tibia: β : .17 [0.02; 0.31], r 2 = 0.49, P = .03), after adjustment for smoking and diabetes status.

The 2 subgroups did not differ significantly in WOMAC or AcroQoL scores (data not shown).

When cross-correlating joint- and bone-related parameters, SDI was found to be positively associated with wrist joint volume (radioscaphoid: β : .01 [0.00; 0.02], r 2 = 0.36, P = .03; radiolunate: β : .02 [0.00; 0.04], r 2 = 0.40, P = .04) ( Fig. 4 ) in the acromegaly group, while the total number of osteophytes was negatively associated with BMSi ( β : −.03 [0.06; 0.00], P = .05); no such associations were found in the control group. When correlating HR-pQCT-derived joint and bone parameters, a pattern consistently found across all examined joints was an association between joint volume/width measurements (JSV and JSW) and bone size measurements (CtA, CtPm, and TbA); no associations to microstructural bone parameters (TbvBMD, TbTh, TbN, and TbSp) were found (data not shown).

Discussion

In this study on patients with long-standing, biochemically controlled acromegaly, we have demonstrated a significantly increased burden of joint disease and markedly reduced trabecular bone quality, as defined by HR-pQCT-derived measures. Osteophytosis, particularly in the MCP joints, was highly prevalent in participants with acromegaly, and the maximum joint space width was increased, as was subjective joint pain. Trabecular bone quality was significantly reduced in the acromegaly group, with lower trabecular vBMD, fewer trabeculae, increased trabecular separation, decreased trabecular thickness, and lower bone/tissue volume ratio. Participants with acromegaly also exhibited worse outcomes regarding the presence, number, and severity of vertebral deformities, which were associated with arthropathy markers, ie, wrist joint volume. Together, these findings exemplify and further elucidate the interplay between the skeletal and articular system in the setting of long-term, hormonally controlled acromegaly.

To the best of authors' knowledge, this is the first study examining bone quality using as wide an array of diagnostic modalities, and in patients with a disease duration as long as in the present paper. Moreover, we are the first to present HR-pQCT data on osteophyte number and size measurements in acromegaly. Features unique to HR-pQCT, such as the smaller voxel size, enabled us to study minute articular structures such as osteophytes, as well as accurately quantify joint space characteristics, adding new details on the precise size and number of osteophytes in acromegaly to the existing body of evidence, that mainly reports on the presence and anatomical distribution of osteophytes [ 12 , 13 , 15 , 18 ].

Osteophytes were present in 60% of participants with acromegaly, and in larger numbers, compared to controls. This is of clinical relevance, considering that severe osteophytosis correlates with joint pain [ 13 ], an important determinant of reduced quality of life in patients with acromegaly [ 7 , 8 ]. The prevalence of osteophytosis in the present study aligns with what has been found in previous works, where clinical and radiological osteoarthritis of the hand joints has been shown to affect 41-89% of patients with acromegaly, even after long-term remission [ 12 , 13 , 18 ]. In participants with acromegaly, increasing age was positively associated with the total number of hand joint osteophytes; similarly, advanced age has been identified as a risk factor for progression of hand osteoarthritis in acromegaly, also regarding osteophytosis [ 12 ]; a pattern also present in patients with rheumatoid arthritis [ 49 ]. The fact that age was significantly associated with the number of osteophytes in the acromegaly group, but not the control group, supports the notion of an accelerating or compounding effect of (previous) GH excess on periarticular bone that remains even after normalization of GH levels, as previously hypothesized [ 12 , 17 , 56 ].

In addition to osteophytosis of the MCP joints, we found significantly larger values of JSW max in the acromegaly group, with a tendency toward larger joint space volumes and widths across all examined joints. Accurate quantification of joint space characteristics using HR-pQCT has not previously been reported, but our results are in line with the description of classic acromegalic arthropathy as shown in previous studies using conventional radiographs [ 12 , 16-19 ] and magnetic resonance imaging [ 15 ]. Longitudinal studies [ 12 , 13 ] have demonstrated significant radiological joint deterioration, particularly of the hands, even years after disease remission. This aligns well with our results and underscores the pervasive nature of acromegalic arthropathy, affecting joints both large and small, weight-bearing and non-weight-bearing, as we have previously demonstrated in an epidemiological setting [ 10 ].

Participants with acromegaly had a significantly increased risk of having at least one vertebral deformity, and acromegaly correlated significantly with the number and severity of vertebral deformities, as reflected by the SDI. This was mainly driven by Genant grade 1 vertebral deformities, since no differences were found when considering vertebral deformities with Genant grades ≥ 2. Although milder, grade 1 vertebral deformities may still have significance, given that previous studies have shown a propensity for these to progress, and pre-existing vertebral deformities are a risk factor for developing incident deformities [ 34 , 57 ]. Moreover, accumulated mild vertebral fractures may cause increased thoracic kyphosis, and the disability it entails, including back pain, impaired sagittal balance, and accelerated degeneration of spinal joints [ 58 ].

In keeping with the increased risk of vertebral deformities, we found significantly deteriorated HR-pQCT indices of trabecular bone quality in both the tibia and the radius, compared to controls. Notably, our trabecular vBMD and thickness measurements are markedly lower than previously reported (radius: 133-163 mg HA/cm 3 and 0.07-0.071 mm; tibia: 121-175 mg HA/cm 3 and 0.07-0.074 mm, respectively) [ 23 , 31 , 32 , 59 ]. Our findings on trabecular number and separation are consistent with previous studies; specifically, the trabecular number falls at the lower end of the reported range (radius: 1.6-1.93 mm −1 ), while trabecular separation is comparatively higher (radius: 0.43-0.52 mm) [ 23 , 31 , 32 ]. These deviations may be due to differences in study populations, as previous studies included younger patients (mean 40-52 years) with shorter disease duration (mean 5.9-9.6 years) [ 59 ] and patients with active disease [ 23 , 31 , 32 ], while one study included males only [ 31 ]. In contrast, our patient population was comprised of a relatively large proportion of older, postmenopausal women; hence, advanced age and physiological hypogonadism, exacerbated by the effects of GH, may account for the comparatively lower trabecular bone quality we found. Compared to surgically cured acromegaly patients, medically treated patients exhibited worse trabecular bone outcomes, likely reflecting more severe acromegaly and thus higher GH exposure in the latter group, necessitating adjuvant medical treatment; a finding consistent with a previous study on acromegaly patients receiving long-term treatment with pegvisomant [ 60 ]. Persistent GH secretion abnormalities despite medical treatment [ 61 ] may also play a role, and a direct effect of somatostatin analogs on bone formation [ 62 ] cannot be ruled out.

The reduced trabecular bone quality in participants with acromegaly was present even in the setting of normal T-scores, underscoring the reduced utility of DXA scans for assessing bone quality in acromegaly patients [ 23 , 31 , 32 ]. The acromegaly patients in the present study had long-standing disease, mean duration of 13.1 years, and were well-controlled, as reflected by both the normal mean IGF-I SD score and high mean AcroQoL score. Thus, our findings indicate permanent damage to the trabecular bone structure, regardless of disease control, as previously reported [ 63 ]; this is underscored by the fact that bone turnover markers did not differ between patients and controls, indicating no active bone remodeling. Furthermore, vitamin D and PTH levels did not differ between groups, suggesting intact calcium homeostasis in both groups. There was, however, a tendency toward lower sclerostin levels in the acromegaly group, which supports the previously suggested hypothesis of compensatory reduction of sclerostin secretion in patients with acromegaly, to counteract the negative effects of GH and IGF-I on bone quality [ 39 ]—even in well-controlled patients.

We were unable to demonstrate an association between HR-pQCT indices and vertebral fractures, likely due to the limited sample size; however, a previous, larger study was also unable to detect differences in HR-pQCT parameters between patients with and without vertebral fractures [ 23 ]. Conversely, deterioration of several markers of trabecular bone quality (TbN, TbvBMD, and TbSp of the radius) significantly correlated with age in the acromegaly group, but not the control group, suggesting that GH excess accelerates features of the physiological aging of the osteoarticular system.

We found significantly lower cortical porosity at the tibial site in participants with acromegaly, a finding also reported previously [ 64 ], whereas others have found no difference at the tibial site, but a significantly higher porosity at the radial site [ 31 ]. Differences in mechanical load may explain this disparity, as the distal tibia is subjected to mechanical stress to a higher degree, and thus receives more stimuli for bone remodeling [ 65 ], however, this would also be the case for the healthy controls.

Spinal deformity index (SDI) was positively associated with increasing joint space volumes, and total osteophyte number was negatively associated with BMSi in the acromegaly group only. These findings confirm the link between bone and joint disease in acromegaly and illustrate the commonality of the effects of GH excess on multiple osteoarticular structures, both trabecular, cortical, and cartilaginous. This supports the notion [ 66 , 67 ] that bone and joint disease in acromegaly should be considered 2 interconnected parts of the disease complex that is acromegalic osteoarthropathy.

We acknowledge certain limitations to the present study: the cross-sectional design precluded the determination of any causal relationships, and the study lacked statistical power in certain outcomes. Moreover, the small sample size with a high number of endpoints introduces the risk of type I errors, ie, false positive findings, which should be considered when interpreting our results. Furthermore, the study cohort was somewhat heterogenous in some respects, but key factors such as disease duration and hormonal levels were similar across the study sample, and no patients with active disease were included. Finally, an estimate of active acromegaly duration prior to diagnosis and biochemical remission would have strengthened our results, considering the substantial impact of diagnostic delay on bone health in acromegaly [ 68 ]. The strengths of the study include a well-matched control group and the use of several modalities for assessment of osteoarticular quality, thoroughly examining both the cortical and trabecular bone compartments, as well as several measures of joint structure.

In conclusion, joint and bone health is significantly impaired in acromegaly, with osteophytosis and reduced trabecular bone quality as the major components. The correlations between joint- and bone-related parameters support the notion that acromegalic osteoarthropathy can be viewed as an interwoven complex. Our findings indirectly emphasize the importance of early diagnosis and treatment of acromegaly to prevent or alleviate complications.

Acknowledgements

The authors would like to extend their deepest gratitude to the participants of the study, and to Mette Brodersen and Ingelise Leegaard for their assistance in procuring DXA and HR-pQCT images, and biochemical sample analysis.

Funding

No funding was provided for the present study.

Disclosures

The authors have nothing to disclose.

Data availability

The data from the present study are available from the corresponding author upon reasonable request.

References

1 Rosendal C , Arlien-Søborg MC , Nielsen EH , et al The changing landscape of acromegaly—an epidemiological perspective . Rev Endocr Metab Disord . 2024 ; 25 ( 4 ): 691 ‐ 705 . 38337125 10.1007/s11154-024-09875-z

2 Aagaard C , Christophersen AS , Finnerup S , et al The prevalence of acromegaly is higher than previously reported: changes over a three-decade period . Clin Endocrinol (Oxf) . 2022 ; 97 ( 6 ): 773 ‐ 782 . 36163677 10.1111/cen.14828 PMC9827885

3 Ben-Shlomo A , Melmed S . Acromegaly . Endocrinol Metab Clin North Am . 2008 ; 37 ( 1 ): 101 ‐ 122 , viii . 18226732 10.1016/j.ecl.2007.10.002 PMC2697616

4 Giustina A , Barkan A , Beckers A , et al A consensus on the diagnosis and treatment of acromegaly comorbidities: an update . J Clin Endocrinol Metab . 2020 ; 105 ( 4 ): E937 ‐ E946 . 10.1210/clinem/dgz096 31606735

5 Matthesen AT , Rosendal C , Christensen EH , et al Psychiatric morbidity in acromegaly: a cohort study and meta-analysis of the literature . Pituitary . 2025 ; 28 ( 2 ): 42 . 40082297 10.1007/s11102-025-01509-0 PMC11906539

6 Störmann S , Cuny T . The socioeconomic burden of acromegaly . Eur J Endocrinol . 2023 ; 189 ( 2 ): R1 ‐ R10 . 10.1093/ejendo/lvad097 37536267

7 Alito A , Basile GC , Bruschetta D , et al Association between pain, arthropathy and health-related quality of life in patients suffering from acromegaly. A cross-sectional study . Folia Med (Plovdiv) . 2023 ; 65 ( 1 ): 37 ‐ 45 . 36855972 10.3897/folmed.65.e68278

8 Biermasz NR , Pereira AM , Smit JWA , Romijn JA , Roelfsema F . Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life . J Clin Endocrinol Metab . 2005 ; 90 ( 5 ): 2731 ‐ 2739 . 15741257 10.1210/jc.2004-2297

9 Dal J , Feldt-Rasmussen U , Andersen M , et al Acromegaly incidence, prevalence, complications and long-term prognosis: a nationwide cohort study . Eur J Endocrinol . 2016 ; 175 ( 3 ): 181 ‐ 190 . 27280374 10.1530/EJE-16-0117

10 Rosendal C , Arlien-Søborg MC , Nielsen EH , et al Musculoskeletal disease in acromegaly—a population-based registry study . Eur J Endocrinol . 2025 ; 192 ( 3 ): 308 ‐ 317 . 40079357 10.1093/ejendo/lvaf047

11 Giustina A , Mazziotti G , Canalis E . Growth hormone, insulin-like growth factors, and the skeleton . Endocr Rev . 2008 ; 29 ( 5 ): 535 ‐ 559 . 18436706 10.1210/er.2007-0036 PMC2726838

12 Claessen KMJA , Ramautar SR , Pereira AM , et al Progression of acromegalic arthropathy despite long-term biochemical control: a prospective, radiological study . Eur J Endocrinol . 2012 ; 167 ( 2 ): 235 ‐ 244 . 22645199 10.1530/EJE-12-0147

13 Pelsma ICM , Biermasz NR , van Furth WR , et al Progression of acromegalic arthropathy in long-term controlled acromegaly patients: 9 years of longitudinal follow-up . J Clin Endocrinol Metab . 2021 ; 106 ( 1 ): 188 ‐ 200 . 33099640 10.1210/clinem/dgaa747

14 Pelsma ICM , Kroon HM , Andela CD , et al Approach to the patient with controlled acromegaly and acromegalic arthropathy: clinical diagnosis and management . Pituitary . 2024 ; 27 ( 6 ): 824 ‐ 836 . 39485592 10.1007/s11102-024-01465-1 PMC11632006

15 Claessen KMJA , Canete AN , Bruin D , et al Acromegalic arthropathy in various stages of the disease: an MRI study . Eur J Endocrinol . 2017 ; 176 ( 6 ): 779 ‐ 790 . 28348071 10.1530/EJE-16-1073

16 Claessen KMJA , Kloppenburg M , Kroon HM , Romijn JA , Pereira AM , Biermasz NR . Two phenotypes of arthropathy in long-term controlled acromegaly? A comparison between patients with and without joint space narrowing (JSN) . Growth Horm IGF Res . 2013 ; 23 ( 5 ): 159 ‐ 164 . 23810124 10.1016/j.ghir.2013.05.003

17 Biermasz NR , Van ‘t Klooster R , Wassenaar MJE , et al Automated image analysis of hand radiographs reveals widened joint spaces in patients with long-term control of acromegaly: relation to disease activity and symptoms . Eur J Endocrinol . 2012 ; 166 ( 3 ): 407 ‐ 413 . 22170798 10.1530/EJE-11-0795

18 Wassenaar MJE , Biermasz NR , van Duinen N , et al High prevalence of arthropathy, according to the definitions of radiological and clinical osteoarthritis, in patients with long-term cure of acromegaly: a case-control study . Eur J Endocrinol . 2009 ; 160 ( 3 ): 357 ‐ 365 . 19050166 10.1530/EJE-08-0845

19 Wassenaar MJE , Biermasz NR , Bijsterbosch J , et al Arthropathy in long-term cured acromeagaly is characterised by osteophytes without joint space narrowing: a comparison with generalised osteoarthritis . Ann Rheum Dis . 2011 ; 70 ( 2 ): 320 ‐ 325 . 21131647 10.1136/ard.2010.131698

20 Figueiredo CP , Perez MO , Sales LP , Schett G , Pereira RMR . HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: data from acquisition to impact on treatment indications . Mod Rheumatol . 2021 ; 31 ( 2 ): 294 ‐ 302 . 32735144 10.1080/14397595.2020.1804669

21 Burghardt AJ , Lee CH , Kuo D , et al Quantitative in vivo HR-pQCT imaging of 3D wrist and metacarpophalangeal joint space width in rheumatoid arthritis . Ann Biomed Eng . 2013 ; 41 ( 12 ): 2553 ‐ 2564 . 23887879 10.1007/s10439-013-0871-x PMC3823828

22 Stok KS , Burghardt AJ , Boutroy S , et al Consensus approach for 3D joint space width of metacarpophalangeal joints of rheumatoid arthritis patients using high-resolution peripheral quantitative computed tomography . Quant Imaging Med Surg . 2020 ; 10 ( 2 ): 314 ‐ 325 . 32190559 10.21037/qims.2019.12.11 PMC7063288

23 Ornellas PG , Gama EMF , Mendonça LMC , et al Evaluation of bone density and microstructure by DXA, TBS, and HR-pQCT: an assessment of cortical porosity and its association with vertebral fractures in patients with acromegaly . J Endocrinol Invest . 2025 ; 48 ( 9 ): 2087 ‐ 2095 . 40526264 10.1007/s40618-025-02619-z

24 Sorohan MC , Poiana C . Vertebral fractures in acromegaly: a systematic review . J Clin Med . 2023 ; 12 ( 1 ): 164 . 10.3390/jcm12010164 PMC9821150 36614962

25 Wydra A , Stelmachowska-Banaś M , Czajka-Oraniec I . Skeletal complications in acromegaly . Reumatologia . 2023 ; 61 ( 4 ): 248 ‐ 255 . 37745143 10.5114/reum/169918 PMC10515128

26 Jawiarczyk-Przybyłowska A , Halupczok-Żyła J , Syrycka J , Zembska A , Kuliczkowska-Płaksej J , Bolanowski M . Trabecular bone score and osteoprotegerin as useful tools in the assessment of bone deterioration in acromegaly . Front Endocrinol (Lausanne) . 2022 ; 13 : 862845 . 35528019 10.3389/fendo.2022.862845 PMC9068997

27 Ribeiro de Moura C , Campos Lopes S , Monteiro AM . Determinants of skeletal fragility in acromegaly: a systematic review and meta-analysis . Pituitary . 2022 ; 25 ( 6 ): 780 ‐ 794 . 35867180 10.1007/s11102-022-01256-6

28 Calatayud M , Pérez-Olivares Martín L , Librizzi MS , et al Trabecular bone score and bone mineral density in patients with long-term controlled acromegaly . Clin Endocrinol (Oxf) . 2021 ; 95 ( 1 ): 58 ‐ 64 . 33559169 10.1111/cen.14439

29 Mazziotti G , Maffezzoni F , Frara S , Giustina A . Acromegalic osteopathy . Pituitary . 2017 ; 20 ( 1 ): 63 ‐ 69 . 27709412 10.1007/s11102-016-0758-6

30 Valassi E , Crespo I , Malouf J , et al Reduction of trabecular and cortical volumetric bone mineral density at the proximal femur in patients with acromegaly . Eur J Endocrinol . 2016 ; 174 ( 2 ): 107 ‐ 114 . 26530355 10.1530/EJE-15-0931

31 Silva PPB , Amlashi FG , Yu EW , et al Bone microarchitecture and estimated bone strength in men with active acromegaly . Eur J Endocrinol . 2017 ; 177 ( 5 ): 409 ‐ 420 . 28780520 10.1530/EJE-17-0468

32 Madeira M , Neto LV , De Paula Paranhos Neto F , et al Acromegaly has a negative influence on trabecular bone, but not on cortical bone, as assessed by high-resolution peripheral quantitative computed tomography . J Clin Endocrinol Metab . 2013 ; 98 ( 4 ): 1734 ‐ 1741 . 23482608 10.1210/jc.2012-4073

33 Uygur MM , Yazıcı DD , Buğdaycı O , Yavuz DG . Prevalence of vertebral fractures and serum sclerostin levels in acromegaly . Endocrine . 2021 ; 73 ( 3 ): 667 ‐ 673 . 34019235 10.1007/s12020-021-02751-9

34 Mazziotti G , Bianchi A , Porcelli T , et al Vertebral fractures in patients with acromegaly: a 3-year prospective study . J Clin Endocrinol Metab . 2013 ; 98 ( 8 ): 3402 ‐ 3410 . 23771918 10.1210/jc.2013-1460

35 Bonadonna S , Mazziotti G , Nuzzo M , et al Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women . J Bone Miner Res . 2005 ; 20 ( 10 ): 1837 ‐ 1844 . 16160741 10.1359/JBMR.050603

36 Vestergaard P , Mosekilde L . Fracture risk is decreased in acromegaly—a potential beneficial effect of growth hormone . Osteoporos Int . 2004 ; 15 ( 2 ): 155 ‐ 159 . 14625668 10.1007/s00198-003-1531-z

37 Kim J , Hong N , Choi J , et al Increased risk of hip fracture in patients with acromegaly: a nationwide cohort study in Korea . Endocrinol Metab (Seoul) . 2023 ; 38 ( 6 ): 690 ‐ 700 . 37899569 10.3803/EnM.2023.1782 PMC10764994

38 Kwon H , Han KD , Kim BS , et al Acromegaly and the long-term fracture risk of the vertebra and hip: a national cohort study . Osteoporos Int . 2023 ; 34 ( 9 ): 1591 ‐ 1600 . 37222744 10.1007/s00198-023-06800-z

39 Halupczok-Żyła J , Jawiarczyk-Przybyłowska A , Bolanowski M . Sclerostin and OPG/RANK-L system take part in bone remodeling in patients with acromegaly . Front Endocrinol (Lausanne) . 2024 ; 15 : 1472680 . 39741885 10.3389/fendo.2024.1472680 PMC11685073

40 Pekkolay Z , Klllnç F , Gozel N , Önalan E , Tuzcu AK . Increased Serum sclerostin levels in patients with active acromegaly . J Clin Endocrinol Metab . 2020 ; 105 ( 3 ): dgz254 . 31821453 10.1210/clinem/dgz254

41 Kužma M , Vaňuga P , Ságova I , et al Non-invasive DXA-derived bone structure assessment of acromegaly patients: a cross-sectional study . Eur J Endocrinol . 2019 ; 180 ( 3 ): 201 ‐ 211 . 30566903 10.1530/EJE-18-0881

42 Maffezzoni F , Maddalo M , Frara S , et al High-resolution-cone beam tomography analysis of bone microarchitecture in patients with acromegaly and radiological vertebral fractures . Endocrine . 2016 ; 54 ( 2 ): 532 ‐ 542 . 27601020 10.1007/s12020-016-1078-3

43 Malgo F , Hamdy NAT , Rabelink TJ , et al Bone material strength index as measured by impact microindentation is altered in patients with acromegaly . Eur J Endocrinol . 2017 ; 176 ( 3 ): 339 ‐ 347 . 28077497 10.1530/EJE-16-0808

44 Wong AK . A comparison of peripheral imaging technologies for bone and muscle quantification: a technical review of image acquisition . J Musculoskelet Neuronal Interact . 2016 ; 16 ( 4 ): 265 ‐ 282 . 27973379 PMC5259568

45 Schoeb M , Hamdy NAT , Malgo F , Winter EM , Appelman-Dijkstra NM . Added value of impact microindentation in the evaluation of bone fragility: a systematic review of the literature . Front Endocrinol (Lausanne) . 2020 ; 11 : 15 . 32117052 10.3389/fendo.2020.00015 PMC7020781

46 Osteoporose—Dansk Endokrinologisk Selskab. Osteoporosis - National Guideline by the Danish Endocrine Society . Accessed June 26, 2026. https://endocrinology.dk/nbv/calcium-og-knoglemetabolisme/osteoporose/

47 Vilaca T , Schini M , Harnan S , et al The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: a systematic review and meta-analysis update . Bone . 2020 : 137 : 115457 . 32480023 10.1016/j.bone.2020.115457

48 Rasmussen NH , Dal J , Kvist AV , van den Bergh JP , Jensen MH , Vestergaard P . Bone parameters in T1D and T2D assessed by DXA and HR-pQCT—a cross-sectional study: the DIAFALL study . Bone . 2023 ; 172 : 116753 . 37001628 10.1016/j.bone.2023.116753

49 Stach CM , Bäuerle M , Englbrecht M , et al Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high-resolution computed tomography . Arthritis & Rheumatism . 2010 ; 62 ( 2 ): 330 ‐ 339 . 20112404 10.1002/art.27252

50 Leere JS , Karmisholt J , Robaczyk M , et al Denosumab and cinacalcet for primary hyperparathyroidism (DENOCINA): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet Diabetes Endocrinol . 2020 ; 8 ( 5 ): 407 ‐ 417 . 32333877 10.1016/S2213-8587(20)30063-2

51 Genant HK , Wu CY , van Kuijk C , Nevitt MC . Vertebral fracture assessment using a semiquantitative technique . J Bone Miner Res . 1993 ; 8 ( 9 ): 1137 ‐ 1148 . 8237484 10.1002/jbmr.5650080915

52 Crans GG , Genant HK , Krege JH . Prognostic utility of a semiquantitative spinal deformity index . Bone . 2005 ; 37 ( 2 ): 175 ‐ 179 . 15922683 10.1016/j.bone.2005.04.003

53 Bellamy N , Buchanan W , Goldsmith C , Campbell J , Stitt L . Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee . J Rheumatol . 1988 ; 15 ( 12 ): 1833 ‐ 1840 . 3068365

54 Webb SM , Prieto L , Badia X , et al Acromegaly quality of life questionnaire (ACROQOL) a new health-related quality of life questionnaire for patients with acromegaly: development and psychometric properties . Clin Endocrinol (Oxf) . 2002 ; 57 ( 2 ): 251 ‐ 258 . 12153605 10.1046/j.1365-2265.2002.01597.x

55 Al-Bashaireh AM , Haddad LG , Weaver M , Chengguo X , Kelly DL , Yoon S . The effect of tobacco smoking on bone mass: an overview of pathophysiologic mechanisms . J Osteoporos . 2018 ; 2018 : 1206235 . 30631414 10.1155/2018/1206235 PMC6304634

56 Claessen KMJA , Mazziotti G , Biermasz NR , Giustina A . Bone and joint disorders in acromegaly . Neuroendocrinology . 2016 ; 103 ( 1 ): 86 ‐ 95 . 25633971 10.1159/000375450

57 Claessen KMJA , Kroon HM , Pereira AM , et al Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study . J Clin Endocrinol Metab . 2013 ; 98 ( 12 ): 4808 ‐ 4815 . 24081732 10.1210/jc.2013-2695

58 de Azevedo Oliveira B , Araujo B , dos Santos TM , et al The acromegalic spine: fractures, deformities and spinopelvic balance . Pituitary . 2019 ; 22 ( 6 ): 601 ‐ 606 . 31556014 10.1007/s11102-019-00991-7

59 Kuker AP , Agarwal S , Shane E , et al Persistent deficits in bone quality in treated acromegaly: evidence from assessments of microstructure . J Endocr Soc . 2023 ; 7 ( 10 ): bvad121 . 37809053 10.1210/jendso/bvad121 PMC10553518

60 Kuker AP , Agarwal S , Shane E , et al Long-term pegvisomant therapy of acromegaly: effects on bone density, turnover and microstructure using HRpQCT . J Endocr Soc . 2024 ; 8 ( 6 ): bvae079 . 38715589 10.1210/jendso/bvae079 PMC11074588

61 Neggers SJ , Kopchick JJ , Jørgensen JOL , Van Der Lely AJ . Hypothesis: extra-hepatic acromegaly: a new paradigm? Eur J Endocrinol . 2011 ; 164 ( 1 ): 11 ‐ 16 . 21045065 10.1530/EJE-10-0969

62 Mackie EJ , Trechsel U , Bruns C . Somatostatin receptors are restricted to a subpopulation of osteoblast-like cells during endochondral bone formation . Development . 1990 ; 110 ( 4 ): 1233 ‐ 1239 . 1712702 10.1242/dev.110.4.1233

63 Mazziotti G , Lania AGA , Canalis E . Bone disorders associated with acromegaly: mechanisms and treatment . Eur J Endocrinol . 2019 ; 181 ( 2 ): R45 ‐ R56 . 31100715 10.1530/EJE-19-0184

64 Duan L , Yang S , Wang LJ , et al The negative impacts of acromegaly on bone microstructure not fully reversible . Front Endocrinol (Lausanne) . 2021 : 12 : 738895 . 34603213 10.3389/fendo.2021.738895 PMC8479105

65 Mallorie A , Shine B . Normal bone physiology, remodelling and its hormonal regulation . Surgery (Oxford) . 2022 ; 40 ( 3 ): 163 ‐ 168 .

66 Cellini M , Biamonte E , Mazza M , et al Vertebral fractures associated with spinal sagittal imbalance and quality of life in acromegaly: a radiographic study with EOS 2D/3D technology . Neuroendocrinology . 2021 ; 111 ( 8 ): 775 ‐ 785 . 32980840 10.1159/000511811

67 Jaafar S , Cristofolini G , Morenghi E , et al DXA-derived lumbar bone strain index corrected for kyphosis is associated with vertebral fractures and trabecular bone score in acromegaly . Endocrine . 2024 ; 85 ( 3 ): 1319 ‐ 1326 . 38809345 10.1007/s12020-024-03863-8

68 Chiloiro S , Giampietro A , Gagliardi I , et al Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience . Pituitary . 2022 ; 25 ( 6 ): 831 ‐ 841 . 35922724 10.1007/s11102-022-01266-4 PMC9362053